rs11924644

chr3-14139250-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):c.953C>T(p.Ala318Val) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,614,174 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (13 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.39

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 (MetaRNN=0.009778649).
• BP6: Variant 3-14139250-C-T is Benign according to our data. Variant chr3-14139250-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14139250-C-T is described in Lovd as [Benign]. Variant chr3-14139250-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00572 (871/152314) while in subpopulation AFR AF= 0.0201 (837/41560). AF 95% confidence interval is 0.019. There are 8 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 863 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.953C>T	p.Ala318Val	missense_variant	11/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.953C>T	p.Ala318Val	missense_variant	11/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*983C>T		3_prime_UTR_variant, NMD_transcript_variant	12/13	3

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152196 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00144 AC: 361 AN: 251424 Hom.: 3 AF XY: 0.000979 AC XY: 133 AN XY: 135888

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000594 AC: 869 AN: 1461860 Hom.: 13 Cov.: 31 AF XY: 0.000510 AC XY: 371 AN XY: 727236

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00572 AC: 871 AN: 152314 Hom.: 8 Cov.: 33 AF XY: 0.00549 AC XY: 409 AN XY: 74476

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00677

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	2.1% (n=79 alleles) in AA (ESP) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arrhythmogenic right ventricular dysplasia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 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. -

Sudden cardiac arrest Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.96	L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.12
Sift	Benign	0.69	T
Sift4G	Benign	0.15	T
Polyphen		0.27	B
Vest4		0.45
MVP		0.31
MPC		0.17
ClinPred		0.040	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.51

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: rs11924644; hg19: chr3-14180750; COSMIC: COSV99045636; COSMIC: COSV99045636;