6-7580212-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_004415.4(DSP):c.4022G>A(p.Arg1341His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,962 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4022G>A | p.Arg1341His | missense_variant | Exon 23 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.4022G>A | p.Arg1341His | missense_variant | Exon 23 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.3582+440G>A | intron_variant | Intron 23 of 23 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4022G>A | p.Arg1341His | missense_variant | Exon 23 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.3582+440G>A | intron_variant | Intron 23 of 23 | 1 | ENSP00000396591.2 | ||||
DSP | ENST00000710359.1 | c.4022G>A | p.Arg1341His | missense_variant | Exon 23 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152006Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250638Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135648
GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727214
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74366
ClinVar
Submissions by phenotype
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This missense variant replaces arginine with histidine at codon 1341 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or stillbirth (PMID: 27532257,30615648, 32879264, Fish 2010, dissertation, University of Cape Town). This variant has also been identified in 17/282014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Cardiomyopathy Uncertain:1
This missense variant replaces arginine with histidine at codon 1341 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or stillbirth (PMID: 27532257,30615648, 32879264, Fish 2010, dissertation, University of Cape Town). This variant has also been identified in 17/282014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Identified in patients with DCM in published literature (PMID: 27532257, 37652022); Identified in a patient with polycystic kidney disease (PKD) who developed and died of acute cardiac failure at 8 months old; exome sequencing in this patient identified a pathogenic variant in PKD1, compound heterozygous variants in JPH2, and heterozygous variants in TTN, MAP2K2, and the p.(R1341H) variant in DSP (PMID: 32879264); Identified in a cohort of stillbirths without chromosomal abnormalities in published literature (PMID: 30615648); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 37652022, 32879264, 30615648) -
Cardiovascular phenotype Uncertain:1
The p.R1341H variant (also known as c.4022G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4022. The arginine at codon 1341 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts and a stillbirth cohort; however, clinical details were limited and additional alterations were identified in some cases (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sahlin E et al. PLoS One, 2019 Jan;14:e0210017; Miura A et al. Int Heart J, 2020 Sep;61:1079-1083). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
- -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at