rs1304410089
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_004415.4(DSP):c.423-1G>A variant causes a splice acceptor 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 Lovd as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
DSP
NM_004415.4 splice_acceptor
NM_004415.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.02
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 Pathogenic. Variant got 15 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 1, new splice context is: aaggtttttttctttgcaAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
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.
PP5
?
Variant 6-7559225-G-A is Pathogenic according to our data. Variant chr6-7559225-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.423-1G>A | splice_acceptor_variant | ENST00000379802.8 | |||
DSP | NM_001008844.3 | c.423-1G>A | splice_acceptor_variant | ||||
DSP | NM_001319034.2 | c.423-1G>A | splice_acceptor_variant | ||||
DSP | NM_001406591.1 | c.423-1G>A | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.423-1G>A | splice_acceptor_variant | 1 | NM_004415.4 | P2 | |||
DSP | ENST00000418664.2 | c.423-1G>A | splice_acceptor_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.423-1G>A | splice_acceptor_variant | A2 | |||||
DSP | ENST00000683563.1 | n.315-1G>A | splice_acceptor_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
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_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at