rs121434508
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032273.4(TMEM126A):c.163C>T(p.Arg55Ter) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_032273.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM126A | NM_032273.4 | c.163C>T | p.Arg55Ter | stop_gained | 3/5 | ENST00000304511.7 | |
TMEM126A | NM_001244735.2 | c.-48C>T | 5_prime_UTR_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM126A | ENST00000304511.7 | c.163C>T | p.Arg55Ter | stop_gained | 3/5 | 1 | NM_032273.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135914
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727238
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74422
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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 | Clinical Genetics, Academic Medical Center | - | - - |
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) - |
Autosomal recessive optic atrophy, OPA7 type Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2012 | - - |
TMEM126A-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at