rs774276092
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_024334.3(TMEM43):c.333G>A(p.Pro111=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
TMEM43
NM_024334.3 synonymous
NM_024334.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.459
Genes affected
TMEM43 (HGNC:28472): (transmembrane protein 43) This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP6
?
Variant 3-14131615-G-A is Benign according to our data. Variant chr3-14131615-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 343505.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS2
?
High AC in GnomAdExome4 at 40 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TMEM43 | NM_024334.3 | c.333G>A | p.Pro111= | synonymous_variant | 4/12 | ENST00000306077.5 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TMEM43 | ENST00000306077.5 | c.333G>A | p.Pro111= | synonymous_variant | 4/12 | 1 | NM_024334.3 | P1 | |
| TMEM43 | ENST00000432444.2 | c.*363G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251280Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135874
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727240
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
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 | Invitae | Jan 22, 2024 | This sequence change affects codon 111 of the TMEM43 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TMEM43 protein. This variant is present in population databases (rs774276092, gnomAD 0.006%). 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: 343505). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 09, 2019 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
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RBP_binding_hub_radar
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Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at