rs1043953

Positions:

• chr3-14142258-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024334.3(TMEM43):​c.*463A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 210,958 control chromosomes in the GnomAD database, including 3,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2344 hom., cov: 33)
  • Exomes 𝑓: 0.15 (902 hom.)
• Consequence: TMEM43 NM_024334.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.80

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]

ENSG00000268279 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-14142258-A-G is Benign according to our data. Variant chr3-14142258-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 343518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
TMEM43	NM_024334.3	c.*463A>G		3_prime_UTR_variant	12/12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5	c.*463A>G		3_prime_UTR_variant	12/12	1	NM_024334.3	ENSP00000303992.5
ENSG00000268279	ENST00000608606.1	n.235+2961A>G		intron_variant		5		ENSP00000476275.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23526 AN: 152090 Hom.: 2344 Cov.: 33

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0955

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.153 AC: 8963 AN: 58750 Hom.: 902 Cov.: 0 AF XY: 0.147 AC XY: 4521 AN XY: 30782

Gnomad4 AFR exome AF: 0.0408

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0937

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.155 AC: 23526 AN: 152208 Hom.: 2344 Cov.: 33 AF XY: 0.154 AC XY: 11425 AN XY: 74412

Gnomad4 AFR AF: 0.0516

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0960

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.182

Alfa AF: 0.199 Hom.: 3205

Bravo AF: 0.144

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.25
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1043953; hg19: chr3-14183758;