rs780299346
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_024334.3(TMEM43):c.859C>T(p.His287Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H287Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.859C>T | p.His287Tyr | missense_variant | 10/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.859C>T | p.His287Tyr | missense_variant | 10/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*889C>T | 3_prime_UTR_variant, NMD_transcript_variant | 11/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250388Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135424
GnomAD4 exome AF: 0.0000451 AC: 66AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 727226
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74384
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2023 | This missense variant replaces histidine with tyrosine at codon 287 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TMEM43-related disorders in the literature. This variant has been identified in 1/250388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 15, 2019 | - - |
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | This missense variant replaces histidine with tyrosine at codon 287 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 29247119), as well as in an individual who did not have cardiovascular symptoms (PMID: 31604776). This variant has been identified in 1/250388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 287 of the TMEM43 protein (p.His287Tyr). This variant is present in population databases (rs780299346, gnomAD 0.0009%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 202121). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2019 | Reported in a patient with sudden unexplained death; however, no additional clinical information was provided (Lin et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 202121; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at