3-14130836-G-A

Position:

• chr3-14130836-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PVS1_Strong PM2 BP6_Moderate

The NM_001407278.1(TMEM43):​c.163-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM43 NM_001407278.1 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.85

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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10016835 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.3, offset of -15, new splice context is: ccactcccctttgctcccAGggc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-14130836-G-A is Benign according to our data. Variant chr3-14130836-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534763.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3	c.177G>A	p.Lys59Lys	synonymous_variant	3/12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5	c.177G>A	p.Lys59Lys	synonymous_variant	3/12	1	NM_024334.3	ENSP00000303992.5
TMEM43	ENST00000432444.2	n.*207G>A		non_coding_transcript_exon_variant	4/13	3		ENSP00000395617.1
TMEM43	ENST00000432444.2	n.*207G>A		3_prime_UTR_variant	4/13	3		ENSP00000395617.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.0
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553602938; hg19: chr3-14172336;