rs727504738
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004415.4(DSP):c.491_492delinsAGCTCGAGTCCCTCG(p.Ala164GlufsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A164A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
DSP
NM_004415.4 frameshift
NM_004415.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.45
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-7559294-CC-AGCTCGAGTCCCTCG is Pathogenic according to our data. Variant chr6-7559294-CC-AGCTCGAGTCCCTCG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179249.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.491_492delinsAGCTCGAGTCCCTCG | p.Ala164GlufsTer23 | frameshift_variant | 4/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.491_492delinsAGCTCGAGTCCCTCG | p.Ala164GlufsTer23 | frameshift_variant | 4/24 | ||
DSP | NM_001319034.2 | c.491_492delinsAGCTCGAGTCCCTCG | p.Ala164GlufsTer23 | frameshift_variant | 4/24 | ||
DSP | NM_001406591.1 | c.491_492delinsAGCTCGAGTCCCTCG | p.Ala164GlufsTer23 | frameshift_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.491_492delinsAGCTCGAGTCCCTCG | p.Ala164GlufsTer23 | frameshift_variant | 4/24 | 1 | NM_004415.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2013 | The Ala164fs variant in DSP has not been reported in individuals with cardiomyop athy or in large population studies. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 164 and lead to a pre mature termination codon 23 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Frameshift and nonsense variants in DSP are common in patients with ARVC (http://arvcdatabase.info/), but recent evidence supports that they can also cause DCM (Elliott 2010, Garcia-Pavia 2011 ). In summary, this variant is likely to be pathogenic, though additional studie s are required to fully establish its clinical significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at