6-7571534-A-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate
The NM_004415.4(DSP):c.1853A>C(p.His618Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H618Y) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 5.79
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_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_004415.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-7571534-A-C is Pathogenic according to our data. Variant chr6-7571534-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372126.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.1853A>C | p.His618Pro | missense_variant | 14/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.1853A>C | p.His618Pro | missense_variant | 14/24 | ||
DSP | NM_001008844.3 | c.1853A>C | p.His618Pro | missense_variant | 14/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.1853A>C | p.His618Pro | missense_variant | 14/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.1853A>C | p.His618Pro | missense_variant | 14/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.1853A>C | p.His618Pro | missense_variant | 14/24 | A2 | |||
DSP | ENST00000684395.1 | n.237A>C | non_coding_transcript_exon_variant | 2/5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 22, 2016 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects DSP function (PMID: 26604139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 372126). This missense change has been observed in individual(s) with autosomal dominant DSP-related conditions (PMID: 26604139). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 618 of the DSP protein (p.His618Pro). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0674);Gain of disorder (P = 0.0674);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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