rs1553603146

Positions:

• chr3-14134812-C-A
• chr3-14134812-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024334.3(TMEM43):​c.626C>A​(p.Ser209Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. S209A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30908298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3	c.626C>A	p.Ser209Tyr	missense_variant	8/12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5	c.626C>A	p.Ser209Tyr	missense_variant	8/12	1	NM_024334.3	ENSP00000303992	P1
TMEM43	ENST00000432444.2	c.*656C>A		3_prime_UTR_variant, NMD_transcript_variant	9/13	3		ENSP00000395617

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The p.S209Y variant (also known as c.626C>A), located in coding exon 8 of the TMEM43 gene, results from a C to A substitution at nucleotide position 626. The serine at codon 209 is replaced by tyrosine, an amino acid with dissimilar properties. An alternate substitution at this position, p.S209A, was reported in an individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arrhythmogenic right ventricular dysplasia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2023

This missense variant replaces serine with tyrosine at codon 209 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 not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.068
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.013	D
Polyphen		0.35	B
Vest4		0.40
MutPred		0.42		Loss of disorder (P = 0.005);
MVP		0.33
MPC		0.23
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553603146; hg19: chr3-14176312;