3-14135891-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024334.3(TMEM43):​c.865G>C​(p.Gly289Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.77
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM43NM_024334.3 linkc.865G>C p.Gly289Arg missense_variant Exon 10 of 12 ENST00000306077.5 NP_077310.1 Q9BTV4A0A024R2F9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM43ENST00000306077.5 linkc.865G>C p.Gly289Arg missense_variant Exon 10 of 12 1 NM_024334.3 ENSP00000303992.5 Q9BTV4
ENSG00000268279ENST00000608606.1 linkn.100G>C non_coding_transcript_exon_variant Exon 2 of 5 5 ENSP00000476275.1 V9GY05
TMEM43ENST00000432444.2 linkn.*895G>C non_coding_transcript_exon_variant Exon 11 of 13 3 ENSP00000395617.1 F8WDL3
TMEM43ENST00000432444.2 linkn.*895G>C 3_prime_UTR_variant Exon 11 of 13 3 ENSP00000395617.1 F8WDL3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461680
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.99
D
Vest4
0.78
MutPred
0.87
Gain of solvent accessibility (P = 0.0584);
MVP
0.57
MPC
0.42
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.65
gMVP
0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-14177391; API