Genetic Variant TMEM43:p.Pro74Pro (chr3-14130881-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_024334.3(TMEM43):c.222C>T(p.Pro74Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,732 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 130 hom. )

Consequence

TMEM43
NM_024334.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -3.02

Publications

7 publications found

Variant links:

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)

TMEM43 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 3-14130881-C-T is Benign according to our data. Variant chr3-14130881-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.02 with no splicing effect.

BS2

High AC in GnomAd4 at 1235 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM43	NM_024334.3	MANE Select	c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	NP_077310.1	Q9BTV4
TMEM43	NM_001407274.1		c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	NP_001394203.1
TMEM43	NM_001407275.1		c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	NP_001394204.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM43	ENST00000306077.5	TSL:1 MANE Select	c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	ENSP00000303992.5	Q9BTV4
TMEM43	ENST00000949127.1		c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	ENSP00000619186.1
TMEM43	ENST00000926410.1		c.222C>T	p.Pro74Pro	synonymous	Exon 3 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes

AF:

0.00812

AC:

1235

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00806

AC:

2023

AN:

251050

AF XY:

0.00812

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00510

Gnomad ASJ exome

AF:

0.00616

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.00930

GnomAD4 exome

AF:

0.0115

AC:

16753

AN:

1461458

Hom.:

130

Cov.:

AF XY:

0.0112

AC XY:

8152

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33474

American (AMR)

AF:

0.00571

AC:

255

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00658

AC:

172

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00204

AC:

176

AN:

86204

European-Finnish (FIN)

AF:

0.00371

AC:

198

AN:

53374

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0137

AC:

15276

AN:

1111772

Other (OTH)

AF:

0.00924

AC:

558

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

909

1818

2727

3636

4545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00811

AC:

1235

AN:

152274

Hom.:

Cov.:

AF XY:

0.00755

AC XY:

562

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00258

AC:

107

AN:

41542

American (AMR)

AF:

0.00712

AC:

109

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00248

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0138

AC:

936

AN:

68012

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00826

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0146

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (4)

Arrhythmogenic right ventricular dysplasia 5 (2)

Cardiomyopathy (2)

Arrhythmogenic right ventricular dysplasia 5;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3 (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.079

(source)

DANN

Benign

0.77

PhyloP100

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over