rs2733587

Variant names:

• chr3-14136454-G-A
• rs2733587
• NM_024334.3:c.882+546G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

TMEM43 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• auditory neuropathy, autosomal dominant 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Emery-Dreifuss muscular dystrophy 7, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000268279 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TMEM43	NM_024334.3	c.882+546G>A		intron_variant	Intron 10 of 11	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5	c.882+546G>A		intron_variant	Intron 10 of 11	1	NM_024334.3	ENSP00000303992.5
ENSG00000268279	ENST00000608606.1	n.117+546G>A		intron_variant	Intron 2 of 4	5		ENSP00000476275.1
TMEM43	ENST00000432444.2	n.*912+546G>A		intron_variant	Intron 11 of 12	3		ENSP00000395617.1
TMEM43	ENST00000713947.1	n.518+546G>A		intron_variant	Intron 4 of 5

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

African (AFR) AF: 0.0270 AC: 1123 AN: 41552

American (AMR) AF: 0.145 AC: 2223 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0976 AC: 339 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1829 AN: 5160

South Asian (SAS) AF: 0.113 AC: 544 AN: 4824

European-Finnish (FIN) AF: 0.124 AC: 1310 AN: 10604

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.130 AC: 8813 AN: 68010

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.121 Hom.: 1531

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
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2733587; hg19: chr3-14177954;