rs727502996
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004415.4(DSP):c.170+5G>A variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Consequence
DSP
NM_004415.4 splice_donor_5th_base, intron
NM_004415.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.76
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.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.170+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000379802.8 | |||
DSP-AS1 | NR_183331.1 | n.38+956C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.170+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_004415.4 | P2 | |||
DSP-AS1 | ENST00000690863.2 | n.344+681C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2014 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2023 | 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: 163233). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the DSP gene. It does not directly change the encoded amino acid sequence of the DSP protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at