6-7579686-GAGA-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_004415.4(DSP):βc.3499_3501delβ(p.Lys1167del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
DSP
NM_004415.4 inframe_deletion
NM_004415.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004415.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 | ||
DSP | NM_001319034.2 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.3499_3501del | p.Lys1167del | inframe_deletion | 23/24 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461658Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727118
GnomAD4 exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 18, 2023 | ClinVar contains an entry for this variant (Variation ID: 534287). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 variant, c.3499_3501del, results in the deletion of 1 amino acid(s) of the DSP protein (p.Lys1167del), but otherwise preserves the integrity of the reading frame. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2020 | The c.3499_3501delAAG variant (also known as p.K1167del) is located in coding exon 23 of the DSP gene. This variant results from an in-frame AAG deletion at nucleotide positions 3499 to 3501. This results in the in-frame deletion of a lysine at codon 1167. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at