6-7558264-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004415.4(DSP):c.422G>C(p.Arg141Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141S) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | ||
DSP | NM_001008844.3 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | ||
DSP | NM_001406591.1 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.422G>C | p.Arg141Thr | missense_variant, splice_region_variant | 3/24 | A2 | |||
DSP | ENST00000683563.1 | n.314G>C | splice_region_variant, non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 141 of the DSP protein (p.Arg141Thr). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 572009). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at