rs727503001

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000379802.8(DSP):​c.3630T>A​(p.Tyr1210Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DSP
ENST00000379802.8 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.02
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 6-7579820-T-A is Pathogenic according to our data. Variant chr6-7579820-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.3630T>A p.Tyr1210Ter stop_gained 23/24 ENST00000379802.8 NP_004406.2
DSPNM_001319034.2 linkuse as main transcriptc.3630T>A p.Tyr1210Ter stop_gained 23/24 NP_001305963.1
DSPNM_001008844.3 linkuse as main transcriptc.3582+48T>A intron_variant NP_001008844.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.3630T>A p.Tyr1210Ter stop_gained 23/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.3582+48T>A intron_variant 1 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.3630T>A p.Tyr1210Ter stop_gained 23/24 ENSP00000518230 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 16, 2013The Tyr1210X variant in DSP has not been reported in individuals with cardiomyop athy or in large population studies. This nonsense variant leads to a premature termination codon at position 1210, which is predicted to lead to a truncated or absent protein. Frameshift and nonsense variants in DSP have been reported in p atients with ARVC (http://arvcdatabase.info/) and DCM (Elliott 2010, Garcia-Pavi a 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 14, 2023For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr1210*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or epidermolysis bullosa (PMID: 29633331, 31737537, 32372669). ClinVar contains an entry for this variant (Variation ID: 163265). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 12, 2024Identified in individuals with features of desmoplakin cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 31737537, 32372669); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32372669, 31737537, 29633331) -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 24, 2023The p.Y1210* pathogenic mutation (also known as c.3630T>A), located in coding exon 23 of the DSP gene, results from a T to A substitution at nucleotide position 3630. This changes the amino acid from a tyrosine to a stop codon within coding exon 23. This alteration has been reported in subjects with dilated cardiomyopathy (DCM) and has been reported in an exome sequencing cohort (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Ambry internal data). This alteration has also been reported as a compound heterozygote in a child with skin erosions, alopecia, nail dystrophy, follicular hyperkeratosis and palmoplantar keratoderma (Bari O et al. Pediatr Dermatol, 2018 Jul;35:e218-e220). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in additional patients with ARVC and DCM (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A;D
Vest4
0.90
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503001; hg19: chr6-7580053; API