rs2733587

Positions:

• chr3-14136454-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024334.3(TMEM43):​c.882+546G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,230 control chromosomes in the GnomAD database, including 1,324 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1324 hom., cov: 33)
• Consequence: TMEM43 NM_024334.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.112

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3	c.882+546G>A		intron_variant		ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5	c.882+546G>A		intron_variant		1	NM_024334.3	ENSP00000303992	P1
TMEM43	ENST00000432444.2	c.*912+546G>A		intron_variant, NMD_transcript_variant		3		ENSP00000395617

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16815 AN: 152112 Hom.: 1327 Cov.: 33

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0976

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.111 AC: 16822 AN: 152230 Hom.: 1324 Cov.: 33 AF XY: 0.110 AC XY: 8223 AN XY: 74424

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0976

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.119

Alfa AF: 0.124 Hom.: 1195

Bravo AF: 0.112

Asia WGS AF: 0.197 AC: 683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.58

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: rs2733587; hg19: chr3-14177954;