rs34099410

Positions:

• chr3-14130881-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024334.3(TMEM43):​c.222C>T​(p.Pro74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,732 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (130 hom.)
• Consequence: TMEM43 NM_024334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.02

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-14130881-C-T is Benign according to our data. Variant chr3-14130881-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14130881-C-T is described in Lovd as [Benign]. Variant chr3-14130881-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (1235/152274) while in subpopulation NFE AF= 0.0138 (936/68012). AF 95% confidence interval is 0.013. There are 11 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.222C>T	p.Pro74=	synonymous_variant	3/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.222C>T	p.Pro74=	synonymous_variant	3/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*252C>T		3_prime_UTR_variant, NMD_transcript_variant	4/13	3

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152156 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00806 AC: 2023 AN: 251050 Hom.: 23 AF XY: 0.00812 AC XY: 1102 AN XY: 135672

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00510

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.0115 AC: 16753 AN: 1461458 Hom.: 130 Cov.: 31 AF XY: 0.0112 AC XY: 8152 AN XY: 726968

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00571

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152274 Hom.: 11 Cov.: 32 AF XY: 0.00755 AC XY: 562 AN XY: 74444

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.0122 Hom.: 22

Bravo AF: 0.00826

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0146

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2008	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TMEM43: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

Arrhythmogenic right ventricular dysplasia 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Arrhythmogenic right ventricular dysplasia 5;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.079
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34099410; hg19: chr3-14172381; COSMIC: COSV60146036; COSMIC: COSV60146036;