rs112242645
Variant names:
Your query was ambiguous. Multiple possible variants found:
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
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 3.05
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.36748296).
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
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GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250638Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135648
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GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727214
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GnomAD4 genome AF: 0.0000789 AC: 12AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74366
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 16, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2024 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at