chr3-14134878-C-T
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2
The NM_024334.3(TMEM43):c.692C>T(p.Pro231Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,148 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P231P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
TMEM43
NM_024334.3 missense
NM_024334.3 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 6.52
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.34119213).
BP6
?
Variant 3-14134878-C-T is Benign according to our data. Variant chr3-14134878-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000465 (68/1461854) while in subpopulation AMR AF= 0.000939 (42/44724). AF 95% confidence interval is 0.000714. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.692C>T | p.Pro231Leu | missense_variant | 8/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.692C>T | p.Pro231Leu | missense_variant | 8/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*722C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 251310Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135836
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727226
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2022 | Variant summary: TMEM43 c.692C>T (p.Pro231Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251310 control chromosomes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.692C>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a predominant consensus as likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 31, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918, 27535533) - |
Arrhythmogenic right ventricular dysplasia 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2021 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0371);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at