rs139590716

Positions:

chr3-14139193-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024334.3(TMEM43):c.896G>C(p.Arg299Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016725272).

BP6

Variant 3-14139193-G-C is Benign according to our data. Variant chr3-14139193-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 202109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152324) while in subpopulation EAS AF= 0.00444 (23/5184). AF 95% confidence interval is 0.00303. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.896G>C	p.Arg299Thr	missense_variant	11/12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.896G>C	p.Arg299Thr	missense_variant	11/12	1	NM_024334.3	ENSP00000303992	P1
TMEM43	ENST00000432444.2 linkuse as main transcript	c.*926G>C		3_prime_UTR_variant, NMD_transcript_variant	12/13	3		ENSP00000395617

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000489

AC:

123

AN:

251436

Hom.:

AF XY:

0.000449

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00533

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000356

AC:

521

AN:

1461650

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

249

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00630

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000212

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000276

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00444

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000309

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2018	Variant summary: TMEM43 c.896G>C (p.Arg299Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function (MutationTaster not captured due to low p-value). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 520-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.896G>C, has been reported in the literature in individuals affected with Arrhythmia (Honda_2016, Liang_2011), predominantly observed with another TMEM43 variant, p.V89M (reported by ClinVar as likely benign). In addition, an unaffected mother was found to carry the variant and the V89M variant, showing a lack of cosegregation with disease (Liang_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 04, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 13, 2021

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 11, 2018

- -

TMEM43-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

TMEM43: BP4, BS1, BS2 -

Arrhythmogenic right ventricular dysplasia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2019

This alteration is classified as likely 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

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0030

Eigen

Benign

-0.11

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.026

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.64

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.66

REVEL

Benign

0.13

Sift

Benign

0.11

Sift4G

Benign

0.22

Polyphen

0.49

Vest4

0.82

MVP

0.27

MPC

0.25

ClinPred

0.045

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.083

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over