GeneBe

rs397516940

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004415.4(DSP):​c.4531C>T​(p.Gln1511Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,826 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DSP
NM_004415.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.23
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 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-7580721-C-T is Pathogenic according to our data. Variant chr6-7580721-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 44914.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.4531C>T p.Gln1511Ter stop_gained 23/24 ENST00000379802.8 NP_004406.2
DSPNM_001008844.3 linkuse as main transcriptc.3582+949C>T intron_variant NP_001008844.1
DSPNM_001319034.2 linkuse as main transcriptc.4050+481C>T intron_variant NP_001305963.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.4531C>T p.Gln1511Ter stop_gained 23/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.3582+949C>T intron_variant 1 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.4050+481C>T intron_variant ENSP00000518230 A2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
249842
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135242
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000500
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461694
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000230
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 31, 2023This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26569459, 31386562), in one individual affected with dilated cardiomyopathy (PMID: 31317183), and in one individual suspected of having hereditary cardiomyopathies (PMID: 35083019). This variant has been identified in 5/249842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 22, 2023This variant is present in population databases (rs397516940, gnomAD 0.05%). This sequence change creates a premature translational stop signal (p.Gln1511*) 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 premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 31386562). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44914). -
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 23, 2015The p.Gln1511X variant in DSP has been previously identified by our laboratory i n 1 adult with features of HCM and ARVC as well as right bundle branch block (RB BB). It has also been identified in 4/65986 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516940). This nonsense variant leads to a premature termination codon at position 1511, w hich is predicted to lead to a truncated or absent protein. Frameshift and nonse nse variants in DSP have been well reported in patients with ARVC (http://arvcda tabase.info/), but recent evidence supports that they can also cause DCM (Pugh 2 014). In summary, although additional studies are required to fully establish it s clinical significance, the p.Gln1511X variant is likely pathogenic. -
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 23, 2023This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26569459, 31386562), in one individual affected with dilated cardiomyopathy (PMID: 31317183), and in one individual suspected of having hereditary cardiomyopathies (PMID: 35083019). This variant has been identified in 5/249842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 28, 2022Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31317183, 31402444, 32372669, 31386562, 26569459, 33460606, 34352074) -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 30, 2022The p.Q1511* pathogenic mutation (also known as c.4531C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4531. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This alteration has been associated in the literature with cardiovascular disease (Akdis D et al. Heart Rhythm, 2016 Mar;13:731-41; van Lint FHM et al. Circ Genom Precis Med, 2019 08;12:e002467; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 03;21:326-336; Reza N et al. Cardiogenetics, 2022 Mar;12:24-36). 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 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
A;D
Vest4
0.90
GERP RS
5.7

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: rs397516940; hg19: chr6-7580954; API