rs397517382
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_024334.3(TMEM43):c.392+4A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00000959 in 1,459,236 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
TMEM43
NM_024334.3 splice_donor_region, intron
NM_024334.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.8838
2
Clinical Significance
Conservation
PhyloP100: 6.07
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 Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BS2
?
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.392+4A>G | splice_donor_region_variant, intron_variant | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.392+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_024334.3 | P1 | |||
TMEM43 | ENST00000432444.2 | c.*422+4A>G | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1459236Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 726092
GnomAD4 exome
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14
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1459236
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29
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8
AN XY:
726092
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2012 | The 392+4A>G variant in TMEM43 has not been reported in the literature nor previ ously identified by our laboratory. It has also not been detected in 2 large and broad populations (European and African American) screened by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS), which is consistent with a role in disease. This variant is located in the 5' splice region and computatio nal tools do suggest a slight impact to splicing (please note that their accurac y is unknown). Additional information is needed to fully assess the clinical sig nificance of this variant. - |
Arrhythmogenic right ventricular dysplasia 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 46144). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the TMEM43 gene. It does not directly change the encoded amino acid sequence of the TMEM43 protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at