ClinVar Genomic variation as it relates to human health
NM_014168.4(METTL5):c.362A>G (p.Asp121Gly)
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(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014168.4(METTL5):c.362A>G (p.Asp121Gly)
Variation ID: 983495 Accession: VCV000983495.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.1 2: 169821136 (GRCh38) [ NCBI UCSC ] 2: 170677646 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 6, 2020 Apr 15, 2024 May 1, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_014168.4:c.362A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054887.2:p.Asp121Gly missense NM_001293186.2:c.362A>G NP_001280115.1:p.Asp121Gly missense NM_001293187.2:c.362A>G NP_001280116.1:p.Asp121Gly missense NC_000002.12:g.169821136T>C NC_000002.11:g.170677646T>C - Protein change
- D121G
- Other names
- -
- Canonical SPDI
- NC_000002.12:169821135:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- mutation affecting coding sequence Sequence Ontology [SO:1000054]
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
METTL5 | - | - |
GRCh38 GRCh37 |
27 | 46 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 19, 2022 | RCV001263451.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2023 | RCV001880059.8 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Oct 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual developmental disorder, autosomal recessive 72
(Autosomal recessive inheritance)
Affected status: yes, no
Allele origin:
germline
|
Medical Genetics Laboratory, Gulhane Training and Research Hospital
Accession: SCV001438327.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Comment:
This sequence change replaces aspartate with glycine at codon 121 of the METTL5 protein (p.Asp121Gly).The aspartate residue is highly conserved and there is a large … (more)
This sequence change replaces aspartate with glycine at codon 121 of the METTL5 protein (p.Asp121Gly).The aspartate residue is highly conserved and there is a large physicochemical difference between aspartate and glycine. This variant is present in population databases [rs760916142; 0.000008 (1/120920, ExAC)]. This variant has not been reported in the literature in individuals with METTL5 related disease. In silico analyses are consistent in its predictions as the variant is damaging to the protein structure/function (Mutationtaster:Disease Causing; Provean:Damaging; Revel: Pathogenic; SIFT: Damaging). This variant cosegregate with disease in multiple affected family members. Using ACMG criteria the variant is classified as a “variant of uncertain significance†(PP1, PM2, PP3). 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)
Observation 1:
Number of individuals with the variant: 3
Sex: mixed
Ethnicity/Population group: Afghani
Geographic origin: Turkey
Observation 2:
Number of individuals with the variant: 2
Sex: mixed
Ethnicity/Population group: Afghan
Geographic origin: Turkey
|
|
Likely pathogenic
(Aug 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual developmental disorder, autosomal recessive 72
Affected status: unknown
Allele origin:
inherited
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV003035486.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
|
|
Pathogenic
(Mar 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002258128.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 983495). This missense change has been observed in individuals with clinical features of METTL5-related intellectual disability syndrome (PMID: 31130284, 36305450). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760916142, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 121 of the METTL5 protein (p.Asp121Gly). (less)
|
|
Likely pathogenic
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004147300.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
METTL5: PM2, PM3, PP1:Moderate, PP3
Number of individuals with the variant: 1
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
mutation affecting coding sequence
|
Medical Genetics Laboratory, Gulhane Training and Research Hospital
Accession: SCV001438327.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Three Afghani siblings with a novel homozygous variant and further delineation of the clinical features of METTL5 related intellectual disability syndrome. | Torun D | The Turkish journal of pediatrics | 2022 | PMID: 36305450 |
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
Text-mined citations for rs760916142 ...
HelpRecord last updated Apr 15, 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.