rs2340917

Variant names:

• chr3-14133762-T-C
• rs2340917
• NM_024334.3:c.536T>C

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.536T>C​(p.Met179Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,488 control chromosomes in the GnomAD database, including 92,444 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M179I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10310 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82134 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.13
• Publications: 41 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0180454E-5).
• BP6: Variant 3-14133762-T-C is Benign according to our data. Variant chr3-14133762-T-C is described in ClinVar as Benign. ClinVar VariationId is 46150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.629 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.536T>C	p.Met179Thr	missense	Exon 7 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.539T>C	p.Met180Thr	missense	Exon 7 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.536T>C	p.Met179Thr	missense	Exon 7 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.536T>C	p.Met179Thr	missense	Exon 7 of 12	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.539T>C	p.Met180Thr	missense	Exon 7 of 12	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.536T>C	p.Met179Thr	missense	Exon 7 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54173 AN: 151938 Hom.: 10300 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.379 AC: 95282 AN: 251456 AF XY: 0.368

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.557

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.670

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.326 AC: 476559 AN: 1461432 Hom.: 82134 Cov.: 45 AF XY: 0.326 AC XY: 236741 AN XY: 727038

African (AFR) AF: 0.421 AC: 14087 AN: 33476

American (AMR) AF: 0.545 AC: 24382 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6440 AN: 26132

East Asian (EAS) AF: 0.601 AC: 23873 AN: 39698

South Asian (SAS) AF: 0.408 AC: 35224 AN: 86244

European-Finnish (FIN) AF: 0.309 AC: 16494 AN: 53410

Middle Eastern (MID) AF: 0.238 AC: 1371 AN: 5768

European-Non Finnish (NFE) AF: 0.301 AC: 334390 AN: 1111600

Other (OTH) AF: 0.336 AC: 20298 AN: 60384

GnomAD4 genome AF: 0.357 AC: 54234 AN: 152056 Hom.: 10310 Cov.: 33 AF XY: 0.361 AC XY: 26815 AN XY: 74328

African (AFR) AF: 0.416 AC: 17237 AN: 41484

American (AMR) AF: 0.436 AC: 6658 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3470

East Asian (EAS) AF: 0.648 AC: 3340 AN: 5156

South Asian (SAS) AF: 0.433 AC: 2092 AN: 4826

European-Finnish (FIN) AF: 0.301 AC: 3181 AN: 10582

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19879 AN: 67940

Other (OTH) AF: 0.339 AC: 717 AN: 2114

Alfa AF: 0.319 Hom.: 27972

Bravo AF: 0.373

TwinsUK AF: 0.306 AC: 1135

ALSPAC AF: 0.311 AC: 1199

ESP6500AA AF: 0.406 AC: 1787

ESP6500EA AF: 0.295 AC: 2541

ExAC AF: 0.372 AC: 45200

Asia WGS AF: 0.553 AC: 1918 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	4	Arrhythmogenic right ventricular dysplasia 5 (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Emery-Dreifuss muscular dystrophy 7, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.19
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.021	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.3	N
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MPC		0.076
ClinPred		0.0041	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.38
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2340917; hg19: chr3-14175262; COSMIC: COSV60145167; COSMIC: COSV60145167;