3-14125052-G-A

Position:

• chr3-14125052-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024334.3(TMEM43):​c.-142G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,070,850 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (101 hom., cov: 33)
  • Exomes 𝑓: 0.011 (539 hom.)
• Consequence: TMEM43 NM_024334.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.223

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-14125052-G-A is Benign according to our data. Variant chr3-14125052-G-A is described in ClinVar as [Benign]. Clinvar id is 1276969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3	c.-142G>A		5_prime_UTR_variant	1/12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077	c.-142G>A		5_prime_UTR_variant	1/12	1	NM_024334.3	ENSP00000303992.5
TMEM43	ENST00000432444.2	n.-142G>A		non_coding_transcript_exon_variant	1/13	3		ENSP00000395617.1
TMEM43	ENST00000432444.2	n.-142G>A		5_prime_UTR_variant	1/13	3		ENSP00000395617.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2087 AN: 152240 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0107 AC: 9845 AN: 918492 Hom.: 539 Cov.: 12 AF XY: 0.00990 AC XY: 4674 AN XY: 472114

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.0859

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.0256

Gnomad4 NFE exome AF: 0.000540

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0137 AC: 2094 AN: 152358 Hom.: 101 Cov.: 33 AF XY: 0.0160 AC XY: 1191 AN XY: 74506

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0113 Hom.: 25

Bravo AF: 0.0172

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.6
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17038940; hg19: chr3-14166552; COSMIC: COSV55500803; COSMIC: COSV55500803;