ClinVar Genomic variation as it relates to human health
NM_015909.4(NBAS):c.2951T>G (p.Ile984Ser)
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(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015909.4(NBAS):c.2951T>G (p.Ile984Ser)
Variation ID: 1335897 Accession: VCV001335897.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p24.3 2: 15402288 (GRCh38) [ NCBI UCSC ] 2: 15542412 (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 Mar 28, 2022 May 6, 2023 Aug 23, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015909.4:c.2951T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056993.2:p.Ile984Ser missense NR_052013.3:n.2981T>G non-coding transcript variant NC_000002.12:g.15402288A>C NC_000002.11:g.15542412A>C NG_032964.1:g.164061T>G - Protein change
- I984S
- Other names
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- Canonical SPDI
- NC_000002.12:15402287:A:C
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
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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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NBAS | - | - |
GRCh38 GRCh37 |
2350 | 2429 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV001885311.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2020 | RCV002267779.2 |
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
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002236519.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 984 of the NBAS protein (p.Ile984Ser). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 984 of the NBAS protein (p.Ile984Ser). This variant is present in population databases (rs140841721, gnomAD 0.003%). This missense change has been observed in individual(s) with SOPH syndrome and acute liver failure (PMID: 26073778, 31761904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1335897). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Jul 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Infantile liver failure syndrome 2
Affected status: yes
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921878.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile liver failure syndrome 2. (I) 0106 … (more)
0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile liver failure syndrome 2. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting <i>in silico</i> predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional Sec39 domain. (PMID: 26073778) (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. (PMID: 26073778, PMID: 31761904, Conference Abstract) (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Analysis of this patient's fibroblasts revealed normal NBAS protein levels but significantly reduced p31, its interaction partner (J Christodoulou). (SP) 1101 - Very strong and specific phenotype match for this individual’s daughter. (SP) 1206 - This variant has been shown to be paternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Infantile liver failure syndrome 2
(Autosomal recessive inheritance)
Affected status: yes, not applicable
Allele origin:
germline,
not applicable
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Brain and Mitochondrial Research, Murdoch Children's Research Insitute
Accession: SCV002062063.1
First in ClinVar: Jul 28, 2022 Last updated: Jul 28, 2022 |
Comment:
The NM_015909.3(NBAS):c.2951T>G; p.(Ile984Ser) variant has been identified in three individuals from two families with NBAS-associated RALF (MIM#616483). The variant was present in a large population … (more)
The NM_015909.3(NBAS):c.2951T>G; p.(Ile984Ser) variant has been identified in three individuals from two families with NBAS-associated RALF (MIM#616483). The variant was present in a large population database at a frequency of <0.01% (3 heterozygotes, 0 homozygotes) (gnomAD v2.1.1 (accessed 15/11/2019). Computational evidence for pathogenicity is conflicting with uninformative conservation (100 vertebrates, UCSC, (accessed 15/11/2019). This variant is predicted to result in a missense amino acid change from isoleucine to serine, there is a large physicochemical difference between isoleucine and serine (Grantham Distance of 142). The variant is located in the well-established functional Sec39 domain. Functional studies of patient's fibroblasts revealed normal NBAS protein levels but significantly reduced p31 when in trans with a likely pathogenic missense variant and decreased NBAS protein expression when in trans with a pathogenic nonsense variant. Based on current information this variant has been classified as PATHOGENIC. (less)
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Tissue: fibroblasts
Result:
Functional studies of patient's fibroblasts revealed normal NBAS protein levels but significantly reduced p31 when in trans with a likely pathogenic missense variant and decreased NBAS protein expression when in trans with a pathogenic nonsense variant.
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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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Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients. | Staufner C | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31761904 |
Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy. | Haack TB | American journal of human genetics | 2015 | PMID: 26073778 |
Text-mined citations for rs140841721 ...
HelpRecord last updated Dec 25, 2023
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.