ClinVar Genomic variation as it relates to human health
NM_003905.4(NAE1):c.254G>A (p.Arg85Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003905.4(NAE1):c.254G>A (p.Arg85Gln)
Variation ID: 1206325 Accession: VCV001206325.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 66823596 (GRCh38) [ NCBI UCSC ] 16: 66857499 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 21, 2021 Mar 18, 2023 Jan 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003905.4:c.254G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003896.1:p.Arg85Gln missense NM_001018159.2:c.236G>A NP_001018169.1:p.Arg79Gln missense NM_001018160.2:c.-14G>A 5 prime UTR NM_001286500.2:c.263G>A NP_001273429.1:p.Arg88Gln missense NC_000016.10:g.66823596C>T NC_000016.9:g.66857499C>T - Protein change
- R79Q, R85Q, R88Q
- Other names
- -
- Canonical SPDI
- NC_000016.10:66823595:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NAE1 | - | - |
GRCh38 GRCh37 |
31 | 65 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
no assertion criteria provided
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- | RCV001573848.13 | |
Pathogenic (2) |
no assertion criteria provided
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Jan 27, 2023 | RCV003127992.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800289.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956971.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing, in vitro
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Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
Affected status: yes, not applicable
Allele origin:
inherited,
not applicable
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University Medical Center Utrecht, University Utrecht
Accession: SCV002319227.3
First in ClinVar: Apr 02, 2022 Last updated: Feb 18, 2023 |
Comment:
This variant was found in a homozygote and a compound heterozygote. The compound heterzygote included the pathogenic variant NM_003905.4:c.147G>C.
Observation 1:
Clinical Features:
Hypoplastic ischiopubic ramus (present) , Infection associated neutropenia (present) , Decreased proportion of naive T cells (present) , Increased lymphocyte apoptosis (present) , Transient neutropenia … (more)
Hypoplastic ischiopubic ramus (present) , Infection associated neutropenia (present) , Decreased proportion of naive T cells (present) , Increased lymphocyte apoptosis (present) , Transient neutropenia (present) , Decreased proportion of memory B cells (present) , Recurrent joint dislocation (present) , Large fleshy ears (present) , Hypoplastic ischia (present) , Aplasia/Hypoplasia of the pubic bone (present) , Abnormal B cell count (present) , Abnormal ischium morphology (present) , Facial erythema (present) , Narrow palpebral fissure (present) , Almond-shaped palpebral fissure (present) , Progressive neurologic deterioration (present) , Abnormal shape of the palpebral fissure (present) , Decreased circulating total IgM (present) , Aplasia/Hypoplasia involving the pelvis (present) , Abnormal T cell subset distribution (present) , Neurodegeneration (present) , Abnormal T cell count (present) , Abnormal enchondral ossification (present) , Hepatosplenomegaly (present) , Recurrent skin infections (present) , Abnormal size of the palpebral fissures (present) , Macrotia (present) , Decreased circulating antibody concentration (present) , Mental deterioration (present) , Hypoplasia of the corpus callosum (present) , Small face (present) , Joint laxity (present) , Abnormal circulating immunoglobulin concentration (present) , Abnormal hip bone morphology (present) , Epicanthus (present) , Recurrent respiratory infections (present) , Abnormality of neutrophils (present) , Long philtrum (present) , Aplasia/Hypoplasia of the corpus callosum (present) , Abnormality of the palpebral fissures (present) , Abnormal corpus callosum morphology (present) , Abnormal hard palate morphology (present) , Reduced bone mineral density (present) , Abnormal cerebral subcortex morphology (present) , Abnormal upper lip morphology (present) , Midface retrusion (present) , Abnormal eyelid morphology (present) , Abnormality of bone mineral density (present) , Abnormality of the philtrum (present) , Abnormal ocular adnexa morphology (present) , Abnormal palate morphology (present) , Abnormality of the ocular adnexa (present) , Low-set ears (present) , Abnormal oral morphology (present) , Orofacial cleft (present) , Abnormal oral morphology (present) , Vascular skin abnormality (present) , Abnormal calvaria morphology (present) (less)
Observation 2:
Clinical Features:
Hypoplastic ischiopubic ramus (present) , Developmental stagnation at onset of seizures (present) , Infection associated neutropenia (present) , Decreased proportion of naive T cells (present) … (more)
Hypoplastic ischiopubic ramus (present) , Developmental stagnation at onset of seizures (present) , Infection associated neutropenia (present) , Decreased proportion of naive T cells (present) , Increased lymphocyte apoptosis (present) , Transient neutropenia (present) , Decreased proportion of memory B cells (present) , Recurrent joint dislocation (present) , Developmental stagnation (present) , Hypoplastic pubic bone (present) , Hypoplastic ischia (present) , Aplasia/Hypoplasia of the pubic bone (present) , Abnormal ischium morphology (present) , Facial erythema (present) , Abnormal pubic bone morphology (present) , Narrow palpebral fissure (present) , Almond-shaped palpebral fissure (present) , Progressive neurologic deterioration (present) , Abnormal shape of the palpebral fissure (present) , Aplasia/Hypoplasia involving the pelvis (present) , Abnormal T cell subset distribution (present) , Neurodegeneration (present) , Abnormal T cell count (present) , Abnormal T cell morphology (present) , Abnormal enchondral ossification (present) , Lymphopenia (present) , Abnormal lymphocyte count (present) , Hepatosplenomegaly (present) , Neutropenia (present) , Recurrent urinary tract infections (present) , Abnormal neutrophil count (present) , Abnormal size of the palpebral fissures (present) , Leukopenia (present) , Coarctation of aorta (present) , Hypoplasia of the corpus callosum (present) , Mental deterioration (present) , Joint laxity (present) , Abnormal hip bone morphology (present) , Epicanthus (present) , Abnormal leukocyte count (present) , Recurrent respiratory infections (present) , Abnormality of neutrophils (present) , Abnormal lymphocyte physiology (present) , Erythema (present) , Respiratory tract infection (present) , Abnormal pelvic girdle bone morphology (present) , Abnormal granulocyte morphology (present) , Abnormal myeloid leukocyte morphology (present) , Abnormal bone ossification (present) , Hypertelorism (present) , Cognitive impairment (present) , Aplasia/Hypoplasia of the corpus callosum (present) , Abnormality of the palpebral fissures (present) , Joint dislocation (present) , Abnormal corpus callosum morphology (present) , Ventriculomegaly (present) , Abnormal cerebral white matter morphology (present) , Abnormal pinna morphology (present) , Abnormality of globe location (present) , Abnormality of skin physiology (present) , Reduced bone mineral density (present) , Abnormal cellular phenotype (present) , Abnormal aortic morphology (present) , Abnormality of the spleen (present) , Abnormality of the neck (present) , Abnormal cellular immune system morphology (present) , Abnormality of bone mineral density (present) , Abnormality of the philtrum (present) , Abnormal eyelid morphology (present) , Abnormal respiratory system morphology (present) , Anemia (present) , Abnormal erythrocyte morphology (present) , Abnormal lip morphology (present) , Abnormality of the lymphatic system (present) , Abnormal ocular adnexa morphology (present) , Abnormal palate morphology (present) , Abnormality of the ocular adnexa (present) , Visceromegaly (present) , Aplasia/Hypoplasia of the cerebrum (present) , Frontal bossing (present) , Abnormal shape of the frontal region (present) , Atrial septal defect (present) , Abnormal atrial septum morphology (present) , Abnormal location of ears (present) , Abnormal abdomen morphology (present) , Limitation of joint mobility (present) , Abnormal cardiac atrium morphology (present) , Recurrent infections (present) , Aplasia/Hypoplasia involving the central nervous system (present) , Abnormal appendicular skeleton morphology (present) , Unusual infection (present) , Abnormal liver morphology (present) , Short stature (present) , Abnormal systemic arterial morphology (present) , Abnormal cerebral morphology (present) , Abnormality of the respiratory system (present) , Abnormal forebrain morphology (present) , Abnormality of body height (present) , Generalized abnormality of skin (present) , Abnormality of immune system physiology (present) , Abnormal inflammatory response (present) , Increased inflammatory response (present) , Abnormal morphology of the great vessels (present) , Abnormality of the liver (present) , Abnormality of the mouth (present) , Abnormal joint morphology (present) , Abnormal skull morphology (present) , Abnormality of the outer ear (present) , Vascular skin abnormality (present) , Abnormal midface morphology (present) , Growth delay (present) , Abnormality of joint mobility (present) , Abnormal eye morphology (present) , Seizure (present) , Abnormality of the immune system (present) , Abnormal axial skeleton morphology (present) , Abnormality of the abdominal organs (present) , Abnormality of mental function (present) , Neurodevelopmental abnormality (present) , Morphological central nervous system abnormality (present) , Abnormality of blood and blood-forming tissues (present) , Abnormality of the face (present) , Abnormal nervous system morphology (present) , Abnormal skeletal morphology (present) , Abnormality of the eye (present) , Abnormality of the skeletal system (present) , Abnormality of the head (present) , Abnormality of head or neck (present) , Abnormal vascular morphology (present) , Abnormal calvaria morphology (present) , Growth abnormality (present) , Abnormal nervous system physiology (present) , Abnormality of the nervous system (present) , Abnormal skin morphology (present) , Abnormal calvaria morphology (present) , Abnormality of the forehead (present) , Abnormal ear morphology (present) , Abnormality of the skin (present) , Abnormality of the urinary system physiology (present) , Ear malformation (present) , Abnormality of metabolism/homeostasis (present) , Abnormality of the integument (present) , Abnormal heart morphology (present) , Abnormality of the digestive system (present) , Abnormal cardiovascular system morphology (present) , Abnormality of the vasculature (present) , Abnormality of the urinary system (present) , Abnormality of the genitourinary system (present) , Abnormality of the cardiovascular system (present) , Phenotypic abnormality (present) (less)
Observation 3:
Result:
Western blot in fibroblasts: severely decreased NAE1 expression
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Pathogenic
(Jan 27, 2023)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND ISCHIOPUBIC HYPOPLASIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003841001.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment on evidence:
In a 12-year-old girl (individual 1), born of unrelated Dutch parents, with neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (NEDFIH; 620210), Muffels et al. … (more)
In a 12-year-old girl (individual 1), born of unrelated Dutch parents, with neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (NEDFIH; 620210), Muffels et al. (2023) identified compound heterozygous missense mutations at conserved residues in the NAE1 gene: a c.254G-A transition (c.254G-A, NM_003905.4), resulting in an arg85-to-gln (R85Q) substitution, and a c.147G-C transversion, resulting in a leu49-to-phe substitution (L49F; 603385.0002). The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent. The R85Q variant was found 4 times in gnomAD, whereas L49F was found once. Query through the GeneMatcher program identified another patient, individual 2, a 19-year-old male also of Dutch descent, who carried a homozygous R85Q mutation that was identified through exome sequencing. Western blot analysis of fibroblasts from these 2 patients showed an almost 80% reduction in NAE1 levels compared to controls; the parents of patient 1 had about 50% NAE1 abundance. Patient cells showed a reduction in the ratio of neddylated to non-neddylated cullin (e.g., CUL1, 603134), suggesting that NAE1 deficiency adversely affects function. Patient 1 had drug-resistant seizures and lymphopenia associated with regression. Patient 2 did not have seizures, but showed lymphopenia during infection. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration. | Muffels IJJ | American journal of human genetics | 2023 | PMID: 36608681 |
Text-mined citations for rs752555475 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.