ClinVar Genomic variation as it relates to human health
NM_017849.4(TMEM127):c.410-2A>G
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017849.4(TMEM127):c.410-2A>G
Variation ID: 449954 Accession: VCV000449954.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q11.2 2: 96254117 (GRCh38) [ NCBI UCSC ] 2: 96919855 (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 Dec 19, 2017 Feb 14, 2024 Feb 27, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017849.4:c.410-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001193304.3:c.410-2A>G splice acceptor NM_001407282.1:c.158-2A>G splice acceptor NM_001407283.1:c.158-2A>G splice acceptor NC_000002.12:g.96254117T>C NC_000002.11:g.96919855T>C NG_027695.1:g.16897A>G LRG_528:g.16897A>G LRG_528t1:c.410-2A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:96254116:T: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.
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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
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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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TMEM127 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
720 | 955 |
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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Pathogenic (3) |
criteria provided, single submitter
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May 1, 2017 | RCV000519103.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2018 | RCV001021873.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 27, 2020 | RCV000699788.9 |
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
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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
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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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Pathogenic
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000618440.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
This variant is denoted TMEM127 c.410-2A>G or IVS3-2A>G and consists of an A>G nucleotidesubstitution at the -2 position of intron 3 of the TMEM127 gene. … (more)
This variant is denoted TMEM127 c.410-2A>G or IVS3-2A>G and consists of an A>G nucleotidesubstitution at the -2 position of intron 3 of the TMEM127 gene. This variant destroys a canonical splice acceptor siteand is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published inthe literature. Based on the current evidence, we consider this variant to be pathogenic. (less)
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Likely pathogenic
(Dec 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001183542.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The c.410-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 3 in the TMEM127 gene. This mutation … (more)
The c.410-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 3 in the TMEM127 gene. This mutation has been reported in a homozygous state in an individual diagnosed with bilateral pheochromocytoma at age 31 as well as dysmorphic features and intellectual disability (Eijkelenkamp K et al. Clin. Genet., 2018 May;93:1049-1056). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000828515.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant affecting this nucleotide (c.410-2A>C, also known as IVS3-2A>C) has been determined to be pathogenic (PMID: 25389632, 20154675, 21156949). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed as homozygous in an individual affected with bilateral pheochromocytoma (PMID: 29282712). ClinVar contains an entry for this variant (Variation ID: 449954). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in the last intron (intron 3) of the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. (less)
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Likely pathogenic
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931668.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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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: SCV001951392.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. | Eijkelenkamp K | Clinical genetics | 2018 | PMID: 29282712 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs121908826 ...
HelpRecord last updated Feb 20, 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.