rs1554108287
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004415.4(DSP):βc.4305_4309delβ(p.Thr1436LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. A1435A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004415.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4305_4309del | p.Thr1436LeufsTer2 | frameshift_variant | 23/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3582+723_3582+727del | intron_variant | ||||
DSP | NM_001319034.2 | c.4050+255_4050+259del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4305_4309del | p.Thr1436LeufsTer2 | frameshift_variant | 23/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3582+723_3582+727del | intron_variant | 1 | A2 | ||||
DSP | ENST00000710359.1 | c.4050+255_4050+259del | intron_variant | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461894Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74232
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 464963). 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 creates a premature translational stop signal (p.Thr1436Leufs*2) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). - |
Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 08, 2017 | The p.Thr1436fs variant in DSP has not been previously reported in individuals w ith cardiomyopathy or large population studies. This variant is located within e xon 23 of DSP which undergoes alternative splicing resulting in two isoforms: on e with a shorter and one with a longer form of this exon. This variant is only l ocated in the coding region of the longer isoform. In that transcript, this vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 1436 and leads to a premature termination codon 2 a mino acids downstream. This alteration is then predicted to cause a truncated or absent protein. Loss-of-function variants in the longer form of exon 23 have be en observed in individuals with ARVC and/or DCM, suggesting that loss-of-functio n variants in this region are likely to be disease causing (LMM data). In summar y, although additional studies are required to fully establish its clinical sign ificance, the p.Thr1436fs variant is likely pathogenic. - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 11, 2019 | This variant deletes 5 nucleotides in exon 23 of the DSP gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. - |
Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 27, 2017 | This sequence change deletes 5 nucleotides from exon 23 of the DSP mRNA (c.4305_4309delCACTG), causing a frameshift at codon 1436. This creates a premature translational stop signal (p.Thr1436Leufs*2) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in DSP are known to be pathogenic (PMID: 16061754, 20716751, 24503780). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2024 | The c.4305_4309delCACTG (p.T1436Lfs*2) alteration, located in exon 23 (coding exon 23) of the DSP gene, consists of a deletion of 5 nucleotides from position 4305 to 4309, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart, 2010; Elliott, 2010; Quarta, 2011; Garcia-Pavia, 2011; Rasmussen, 2013; Pugh, 2014). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at