rs35100587

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_024334.3(TMEM43):​c.909C>T​(p.Ser303Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,800 control chromosomes in the GnomAD database, including 430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 40 hom., cov: 33)
Exomes 𝑓: 0.020 ( 390 hom. )

Consequence

TMEM43
NM_024334.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.592
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 3-14139206-C-T is Benign according to our data. Variant chr3-14139206-C-T is described in ClinVar as [Benign]. Clinvar id is 46154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14139206-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.592 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0203 (3093/152308) while in subpopulation SAS AF= 0.0332 (160/4824). AF 95% confidence interval is 0.029. There are 40 homozygotes in gnomad4. There are 1483 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 3093 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM43NM_024334.3 linkuse as main transcriptc.909C>T p.Ser303Ser synonymous_variant 11/12 ENST00000306077.5 NP_077310.1 Q9BTV4A0A024R2F9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM43ENST00000306077.5 linkuse as main transcriptc.909C>T p.Ser303Ser synonymous_variant 11/121 NM_024334.3 ENSP00000303992.5 Q9BTV4
ENSG00000268279ENST00000608606.1 linkuse as main transcriptn.144C>T non_coding_transcript_exon_variant 3/55 ENSP00000476275.1 V9GY05

Frequencies

GnomAD3 genomes
AF:
0.0203
AC:
3086
AN:
152190
Hom.:
40
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0294
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0142
Gnomad ASJ
AF:
0.00691
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0325
Gnomad FIN
AF:
0.0116
Gnomad MID
AF:
0.0475
Gnomad NFE
AF:
0.0188
Gnomad OTH
AF:
0.0239
GnomAD3 exomes
AF:
0.0184
AC:
4637
AN:
251432
Hom.:
69
AF XY:
0.0190
AC XY:
2585
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.0292
Gnomad AMR exome
AF:
0.0104
Gnomad ASJ exome
AF:
0.00575
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0307
Gnomad FIN exome
AF:
0.0114
Gnomad NFE exome
AF:
0.0215
Gnomad OTH exome
AF:
0.0186
GnomAD4 exome
AF:
0.0199
AC:
29155
AN:
1461492
Hom.:
390
Cov.:
31
AF XY:
0.0204
AC XY:
14824
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.0293
Gnomad4 AMR exome
AF:
0.0113
Gnomad4 ASJ exome
AF:
0.00612
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0306
Gnomad4 FIN exome
AF:
0.0137
Gnomad4 NFE exome
AF:
0.0205
Gnomad4 OTH exome
AF:
0.0195
GnomAD4 genome
AF:
0.0203
AC:
3093
AN:
152308
Hom.:
40
Cov.:
33
AF XY:
0.0199
AC XY:
1483
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0294
Gnomad4 AMR
AF:
0.0142
Gnomad4 ASJ
AF:
0.00691
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.0332
Gnomad4 FIN
AF:
0.0116
Gnomad4 NFE
AF:
0.0188
Gnomad4 OTH
AF:
0.0237
Alfa
AF:
0.0199
Hom.:
11
Bravo
AF:
0.0206
Asia WGS
AF:
0.0180
AC:
64
AN:
3478
EpiCase
AF:
0.0219
EpiControl
AF:
0.0231

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 15, 2013- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 12, 2009- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Cardiomyopathy Benign:2
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 18, 2021- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 15, 2018- -
Arrhythmogenic right ventricular dysplasia 5 Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
12
DANN
Benign
0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35100587; hg19: chr3-14180706; API