rs113449357

Variant names:

• chr3-14139231-C-T
• rs113449357
• NM_024334.3:c.934C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-14139231-C-T
• chr3-14139231-C-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024334.3(TMEM43):​c.934C>T​(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,114 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 33)
  • Exomes 𝑓: 0.013 (177 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.62
• Publications: 25 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)

ENSG00000268279 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015833825).
• BP6: Variant 3-14139231-C-T is Benign according to our data. Variant chr3-14139231-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1572 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.934C>T	p.Arg312Trp	missense	Exon 11 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.937C>T	p.Arg313Trp	missense	Exon 11 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.931C>T	p.Arg311Trp	missense	Exon 11 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.934C>T	p.Arg312Trp	missense	Exon 11 of 12	ENSP00000303992.5	Q9BTV4
	ENSG00000268279	ENST00000608606.1	TSL:5	n.169C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000476275.1	V9GY05
	TMEM43	ENST00000949127.1		c.937C>T	p.Arg313Trp	missense	Exon 11 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1574 AN: 152196 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00969 AC: 2436 AN: 251430 AF XY: 0.00985

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.0128 AC: 18663 AN: 1461800 Hom.: 177 Cov.: 31 AF XY: 0.0125 AC XY: 9108 AN XY: 727208

African (AFR) AF: 0.00191 AC: 64 AN: 33480

American (AMR) AF: 0.00351 AC: 157 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00238 AC: 205 AN: 86258

European-Finnish (FIN) AF: 0.0343 AC: 1833 AN: 53414

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0142 AC: 15764 AN: 1111926

Other (OTH) AF: 0.00975 AC: 589 AN: 60396

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152314 Hom.: 13 Cov.: 33 AF XY: 0.0114 AC XY: 849 AN XY: 74462

African (AFR) AF: 0.00226 AC: 94 AN: 41570

American (AMR) AF: 0.00660 AC: 101 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0389 AC: 413 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 884 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0112 Hom.: 31

Bravo AF: 0.00776

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00904 AC: 1098

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	not provided (7)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.78
MPC		0.41
ClinPred		0.066	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.96
Mutation Taster		=71/29	polymorphism

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: rs113449357; hg19: chr3-14180731; COSMIC: COSV104623765; COSMIC: COSV104623765;