rs36083134

chr3-14141688-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):c.1096G>A(p.Ala366Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,614,190 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A366V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (10 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.22

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_024334.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008789092).
• BP6: Variant 3-14141688-G-A is Benign according to our data. Variant chr3-14141688-G-A is described in ClinVar as [Benign]. Clinvar id is 46138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14141688-G-A is described in Lovd as [Benign]. Variant chr3-14141688-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (829/152338) while in subpopulation AFR AF= 0.0187 (778/41568). AF 95% confidence interval is 0.0176. There are 9 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 829 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.1096G>A	p.Ala366Thr	missense_variant	12/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.1096G>A	p.Ala366Thr	missense_variant	12/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*1126G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 829 AN: 152220 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 251390 Hom.: 5 AF XY: 0.00107 AC XY: 145 AN XY: 135876

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000581 AC: 849 AN: 1461852 Hom.: 10 Cov.: 32 AF XY: 0.000517 AC XY: 376 AN XY: 727230

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00544 AC: 829 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00538 AC XY: 401 AN XY: 74496

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000866 Hom.: 1

Bravo AF: 0.00629

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2012	Ala366Thr in exon 12 of TMEM43: This variant is not expected to have clinical si gnificance because it has been identified in 2% (82/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs36083134). Ala366Thr in exon 12 of TMEM43 (rs36083 134; allele frequency = 2%, 82/4406) ** -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 12, 2016	- -

Arrhythmogenic right ventricular dysplasia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0087	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.25	T
Polyphen		0.68	P
Vest4		0.29
MVP		0.31
MPC		0.17
ClinPred		0.012	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.42

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: rs36083134; hg19: chr3-14183188;