rs121434508
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001244735.2(TMEM126A):c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
TMEM126A
NM_001244735.2 5_prime_UTR_premature_start_codon_gain
NM_001244735.2 5_prime_UTR_premature_start_codon_gain
Scores
4
1
2
Clinical Significance
Conservation
PhyloP100: 1.71
Genes affected
TMEM126A (HGNC:25382): (transmembrane protein 126A) The protein encoded by this gene is a mitochondrial membrane protein of unknown function. Defects in this gene are a cause of optic atrophy type 7 (OPA7). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.385
PP5
Variant 11-85654139-C-T is Pathogenic according to our data. Variant chr11-85654139-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-85654139-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM126A | NM_032273.4 | c.163C>T | p.Arg55* | stop_gained | 3/5 | ENST00000304511.7 | NP_115649.1 | |
TMEM126A | NM_001244735.2 | c.-48C>T | 5_prime_UTR_premature_start_codon_gain_variant | 2/4 | NP_001231664.1 | |||
TMEM126A | NM_001244735.2 | c.-48C>T | 5_prime_UTR_variant | 2/4 | NP_001231664.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM126A | ENST00000304511.7 | c.163C>T | p.Arg55* | stop_gained | 3/5 | 1 | NM_032273.4 | ENSP00000306887.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135914
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727238
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74422
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30369941, 28492530, 25525159, 19327736, 20405026, 22815638, 31589614, 33841295, 32855858, 36071901) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | This variant is present in population databases (rs121434508, gnomAD 0.02%). 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 410). This premature translational stop signal has been observed in individual(s) with autosomal recessive optic atrophy (PMID: 19327736, 30369941). This sequence change creates a premature translational stop signal (p.Arg55*) in the TMEM126A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM126A are known to be pathogenic (PMID: 19327736). - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Autosomal recessive optic atrophy, OPA7 type Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2023 | - - |
TMEM126A-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The TMEM126A c.163C>T variant is predicted to result in premature protein termination (p.Arg55*). This variant has been reported in the homozygous state in individuals with optic atrophy from a large multiplex consanguineous Algerian family along with three additional families originating from the same geographic region (Hanein et al. 2009. PubMed ID: 19327736). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at