rs35924492

Variant names:

• chr3-14134884-A-G
• rs35924492
• NM_024334.3:c.698A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):​c.698A>G​(p.Tyr233Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,614,180 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y233Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (15 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.43
• Publications: 9 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=0.013732225).
• BP6: Variant 3-14134884-A-G is Benign according to our data. Variant chr3-14134884-A-G is described in ClinVar as Benign. ClinVar VariationId is 177840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00598 (911/152330) while in subpopulation AFR AF = 0.0211 (878/41584). AF 95% confidence interval is 0.02. There are 5 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 911 AD gene.

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.698A>G	p.Tyr233Cys	missense	Exon 8 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.701A>G	p.Tyr234Cys	missense	Exon 8 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.698A>G	p.Tyr233Cys	missense	Exon 8 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.698A>G	p.Tyr233Cys	missense	Exon 8 of 12	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.701A>G	p.Tyr234Cys	missense	Exon 8 of 12	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.698A>G	p.Tyr233Cys	missense	Exon 8 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 909 AN: 152212 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00155 AC: 390 AN: 251330 AF XY: 0.00106

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000601 AC: 879 AN: 1461850 Hom.: 15 Cov.: 32 AF XY: 0.000523 AC XY: 380 AN XY: 727230

African (AFR) AF: 0.0219 AC: 733 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112000

Other (OTH) AF: 0.00108 AC: 65 AN: 60388

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152330 Hom.: 5 Cov.: 33 AF XY: 0.00577 AC XY: 430 AN XY: 74482

African (AFR) AF: 0.0211 AC: 878 AN: 41584

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00213 Hom.: 10

Bravo AF: 0.00694

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	3	Cardiomyopathy (3)
-	-	1	Arrhythmogenic right ventricular dysplasia 5 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 5;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sudden cardiac arrest (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Benign	0.15	T
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.60
MVP		0.58
MPC		0.33
ClinPred		0.050	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.38
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs35924492; hg19: chr3-14176384; COSMIC: COSV99045634; COSMIC: COSV99045634;