rs371797765
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_024334.3(TMEM43):c.748G>A(p.Gly250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G250G) has been classified as Likely benign.
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.748G>A | p.Gly250Ser | missense_variant | 9/12 | ENST00000306077.5 | NP_077310.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.748G>A | p.Gly250Ser | missense_variant | 9/12 | 1 | NM_024334.3 | ENSP00000303992.5 | ||
TMEM43 | ENST00000432444.2 | n.*778G>A | non_coding_transcript_exon_variant | 10/13 | 3 | ENSP00000395617.1 | ||||
TMEM43 | ENST00000432444.2 | n.*778G>A | 3_prime_UTR_variant | 10/13 | 3 | ENSP00000395617.1 | ||||
ENSG00000268279 | ENST00000608606.1 | n.-18G>A | upstream_gene_variant | 5 | ENSP00000476275.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 249956Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135214
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460392Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 726550
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74472
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 5 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the TMEM43 protein (p.Gly250Ser). This variant is present in population databases (rs371797765, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 466423). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 29, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 11, 2018 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | TMEM43: BP4 - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at