GeneBe

rs28763961

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004415.4(DSP):​c.1481A>T​(p.Tyr494Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00525 in 1,614,238 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y494Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 20 hom., cov: 32)
Exomes 𝑓: 0.0051 ( 252 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

3
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.81
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0030483603).
BP6
Variant 6-7569247-A-T is Benign according to our data. Variant chr6-7569247-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 44860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7569247-A-T is described in Lovd as [Benign]. Variant chr6-7569247-A-T is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/24 ENST00000379802.8 NP_004406.2
DSPNM_001319034.2 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/24 NP_001305963.1
DSPNM_001008844.3 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/24 NP_001008844.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/241 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.1481A>T p.Tyr494Phe missense_variant 12/24 ENSP00000518230 A2

Frequencies

GnomAD3 genomes
AF:
0.00708
AC:
1077
AN:
152226
Hom.:
20
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0188
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.0772
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.0260
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00106
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.0134
AC:
3376
AN:
251464
Hom.:
90
AF XY:
0.0116
AC XY:
1571
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.0366
Gnomad ASJ exome
AF:
0.000595
Gnomad EAS exome
AF:
0.0721
Gnomad SAS exome
AF:
0.00140
Gnomad FIN exome
AF:
0.0245
Gnomad NFE exome
AF:
0.00129
Gnomad OTH exome
AF:
0.00717
GnomAD4 exome
AF:
0.00506
AC:
7404
AN:
1461894
Hom.:
252
Cov.:
32
AF XY:
0.00472
AC XY:
3429
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.0347
Gnomad4 ASJ exome
AF:
0.000421
Gnomad4 EAS exome
AF:
0.0860
Gnomad4 SAS exome
AF:
0.00162
Gnomad4 FIN exome
AF:
0.0251
Gnomad4 NFE exome
AF:
0.000439
Gnomad4 OTH exome
AF:
0.00720
GnomAD4 genome
AF:
0.00706
AC:
1075
AN:
152344
Hom.:
20
Cov.:
32
AF XY:
0.00858
AC XY:
639
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.0187
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.0770
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.0260
Gnomad4 NFE
AF:
0.00106
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00246
Hom.:
2
Bravo
AF:
0.00693
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.0118
AC:
1430
Asia WGS
AF:
0.0290
AC:
100
AN:
3478
EpiCase
AF:
0.000327
EpiControl
AF:
0.000296

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Benign, criteria provided, single submitterclinical testingGeneDxAug 02, 2011This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 26, 2017p.Tyr494Phe in exon 12 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 7.7% (669/8648) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28763961). -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 10, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Benign:2
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 22, 2023- -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 07, 2018- -
Lethal acantholytic epidermolysis bullosa Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Woolly hair-skin fragility syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Arrhythmogenic right ventricular dysplasia 8 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 03, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 09, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D
MetaRNN
Benign
0.0030
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.76
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.23
Sift
Benign
0.086
T;D
Sift4G
Benign
0.22
T;T
Polyphen
0.0060
B;.
Vest4
0.12
MPC
0.20
ClinPred
0.013
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.19
gMVP
0.23

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: rs28763961; hg19: chr6-7569480; COSMIC: COSV65796858; COSMIC: COSV65796858; API