rs8516

Positions:

• chr3-14143169-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024334.3(TMEM43):​c.*1374T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,282 control chromosomes in the GnomAD database, including 2,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2456 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: TMEM43 NM_024334.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.981

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-14143169-T-C is Benign according to our data. Variant chr3-14143169-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 343535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.*1374T>C		3_prime_UTR_variant	12/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.*1374T>C		3_prime_UTR_variant	12/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*2607T>C		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25142 AN: 152162 Hom.: 2456 Cov.: 33

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.165 AC: 25143 AN: 152280 Hom.: 2456 Cov.: 33 AF XY: 0.163 AC XY: 12172 AN XY: 74470

Gnomad4 AFR AF: 0.0890

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0953

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.190

Alfa AF: 0.201 Hom.: 3175

Bravo AF: 0.155

Asia WGS AF: 0.0410 AC: 145 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.50

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: rs8516; hg19: chr3-14184669;