rs201094625

Variant names:

• chr3-14130825-C-T
• rs201094625
• NM_024334.3:c.166C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_024334.3(TMEM43):​c.166C>T​(p.Arg56Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 1.98
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37063575).
• BS2: High AC in GnomAdExome4 at 110 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.166C>T	p.Arg56Cys	missense	Exon 3 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.166C>T	p.Arg56Cys	missense	Exon 3 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.166C>T	p.Arg56Cys	missense	Exon 3 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.166C>T	p.Arg56Cys	missense	Exon 3 of 12	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.166C>T	p.Arg56Cys	missense	Exon 3 of 12	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.166C>T	p.Arg56Cys	missense	Exon 3 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251104 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000753 AC: 110 AN: 1461458 Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50 AN XY: 726970

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111828

Other (OTH) AF: 0.0000497 AC: 3 AN: 60368

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000468 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Arrhythmogenic right ventricular dysplasia 5 (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.0
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.20
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.35	B
Vest4		0.57
MVP		0.39
MPC		0.10
ClinPred		0.27	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.87
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs201094625; hg19: chr3-14172325;