3-14141742-C-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_024334.3(TMEM43):āc.1150C>Gā(p.Leu384Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,208 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L384F) 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 -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.1150C>G | p.Leu384Val | missense_variant | Exon 12 of 12 | ENST00000306077.5 | NP_077310.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.1150C>G | p.Leu384Val | missense_variant | Exon 12 of 12 | 1 | NM_024334.3 | ENSP00000303992.5 | ||
ENSG00000268279 | ENST00000608606.1 | n.235+2445C>G | intron_variant | Intron 3 of 4 | 5 | ENSP00000476275.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152258Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251382Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135884
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727216
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152376Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74510
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the TMEM43 protein (p.Leu384Val). This variant is present in population databases (rs193922706, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TMEM43-related conditions (PMID: 28750076, 31760239; internal data). ClinVar contains an entry for this variant (Variation ID: 36870). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. 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. -
This missense variant replaces leucine with valine at codon 384 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 dilated cardiomyopathy who also carried an additional variant in MYBPC3 (PMID: 28750076). It has also been reported in an individual affected with sudden cardiac death who also carried an additional variant in DSP that appeared to segregate with arrhythmogenic left ventricular cardiomyopathy in an affected child (PMID: 31760239). This variant has been identified in 15/282786 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. -
not specified Uncertain:1
Variant summary: TMEM43 c.1150C>G (p.Leu384Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 277150 control chromosomes (gnomAD). The observed variant frequency is approximately 6.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is benign. c.1150C>G has been reported in the literature in an individual affected with dilated cardiomyopathy (Forleo_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Cardiomyopathy Uncertain:1
This missense variant replaces leucine with valine at codon 384 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 dilated cardiomyopathy who also carried an additional variant in MYBPC3 (PMID: 28750076). It has also been reported in an individual affected with sudden cardiac death who also carried an additional variant in DSP that appeared to segregate with arrhythmogenic left ventricular cardiomyopathy in an affected child (PMID: 31760239). This variant has been identified in 15/282786 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. -
not provided Uncertain:1
Identified in association with dilated cardiomyopathy and sudden death; however, these patients also harbored additional cardiogenetic variants (PMID: 28750076, 31760239); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31760239, 31402444, 28750076) -
Cardiovascular phenotype Benign:1
This alteration is classified as 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