rs1043953

Variant names:

• chr3-14142258-A-G
• rs1043953
• NM_024334.3:c.*463A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• auditory neuropathy, autosomal dominant 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Emery-Dreifuss muscular dystrophy 7, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000268279 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	NM_024334.3	MANE Select	c.*463A>G		3_prime_UTR	Exon 12 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.*463A>G		3_prime_UTR	Exon 12 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.*463A>G		3_prime_UTR	Exon 12 of 12	NP_001394204.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	ENST00000306077.5	TSL:1 MANE Select	c.*463A>G		3_prime_UTR	Exon 12 of 12	ENSP00000303992.5	Q9BTV4
	ENSG00000268279	ENST00000608606.1	TSL:5	n.235+2961A>G		intron	N/A	ENSP00000476275.1	V9GY05
	TMEM43	ENST00000949127.1		c.*463A>G		3_prime_UTR	Exon 12 of 12	ENSP00000619186.1

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

African (AFR) AF: 0.0408 AC: 94 AN: 2304

American (AMR) AF: 0.136 AC: 520 AN: 3810

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 220 AN: 1278

East Asian (EAS) AF: 0.00 AC: 0 AN: 3782

South Asian (SAS) AF: 0.0937 AC: 803 AN: 8574

European-Finnish (FIN) AF: 0.206 AC: 508 AN: 2462

Middle Eastern (MID) AF: 0.126 AC: 27 AN: 214

European-Non Finnish (NFE) AF: 0.188 AC: 6260 AN: 33248

Other (OTH) AF: 0.173 AC: 531 AN: 3078

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

African (AFR) AF: 0.0516 AC: 2145 AN: 41552

American (AMR) AF: 0.153 AC: 2342 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4822

European-Finnish (FIN) AF: 0.241 AC: 2552 AN: 10580

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14545 AN: 68002

Other (OTH) AF: 0.182 AC: 383 AN: 2110

Alfa AF: 0.178 Hom.: 4667

Bravo AF: 0.144

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.25
DANN	Benign	0.67
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1043953;

hg19: chr3-14183758;