3-14141803-C-T

Position:

chr3-14141803-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024334.3(TMEM43):c.*8C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,611,350 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

TMEM43
NM_024334.3 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.0720

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:

ENSG00000268279 (HGNC:):

ENSG00000268279 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 3-14141803-C-T is Benign according to our data. Variant chr3-14141803-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46136.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr3-14141803-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00213 (324/152354) while in subpopulation AFR AF= 0.00748 (311/41590). AF 95% confidence interval is 0.00679. There are 2 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.*8C>T		3_prime_UTR_variant	12/12	ENST00000306077.5	NP_077310.1	Q9BTV4A0A024R2F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.*8C>T		3_prime_UTR_variant	12/12	1	NM_024334.3	ENSP00000303992.5		Q9BTV4
ENSG00000268279	ENST00000608606.1 linkuse as main transcript	n.235+2506C>T		intron_variant		5		ENSP00000476275.1		V9GY05

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

325

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00752

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000518

AC:

128

AN:

247302

Hom.:

AF XY:

0.000372

AC XY:

AN XY:

134258

show subpopulations

Gnomad AFR exome

AF:

0.00742

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000222

AC:

324

AN:

1458996

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

725864

show subpopulations

Gnomad4 AFR exome

AF:

0.00822

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000581

GnomAD4 genome

AF:

0.00213

AC:

324

AN:

152354

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00748

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00261

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2012	8C>T in exon 12 of TMEM43: This variant is not expected to have clinical signif icance because it has been identified in 0.5% (21/4404) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS). 8C>T in exon 12 of TMEM43 (allele frequency = 0.5%, 21/4404) ** -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2014	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 cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 11, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

TMEM43: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.1

DANN

Benign

0.89

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