GeneBe

rs6929069

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.5213G>A​(p.Arg1738Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,616 control chromosomes in the GnomAD database, including 21,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3497 hom., cov: 32)
Exomes 𝑓: 0.15 ( 17540 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.629
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=0.004233688).
BP6
Variant 6-7581403-G-A is Benign according to our data. Variant chr6-7581403-G-A is described in ClinVar as [Benign]. Clinvar id is 44925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7581403-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.5213G>A p.Arg1738Gln missense_variant 23/24 ENST00000379802.8 NP_004406.2
DSPNM_001008844.3 linkuse as main transcriptc.3583-1239G>A intron_variant NP_001008844.1
DSPNM_001319034.2 linkuse as main transcriptc.4050+1163G>A intron_variant NP_001305963.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.5213G>A p.Arg1738Gln missense_variant 23/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.3583-1239G>A intron_variant 1 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.4050+1163G>A intron_variant ENSP00000518230 A2

Frequencies

GnomAD3 genomes
AF:
0.195
AC:
29704
AN:
152008
Hom.:
3491
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.324
Gnomad AMI
AF:
0.0670
Gnomad AMR
AF:
0.179
Gnomad ASJ
AF:
0.152
Gnomad EAS
AF:
0.201
Gnomad SAS
AF:
0.234
Gnomad FIN
AF:
0.178
Gnomad MID
AF:
0.175
Gnomad NFE
AF:
0.125
Gnomad OTH
AF:
0.181
GnomAD3 exomes
AF:
0.172
AC:
43268
AN:
251186
Hom.:
4162
AF XY:
0.170
AC XY:
23120
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.330
Gnomad AMR exome
AF:
0.199
Gnomad ASJ exome
AF:
0.157
Gnomad EAS exome
AF:
0.195
Gnomad SAS exome
AF:
0.237
Gnomad FIN exome
AF:
0.176
Gnomad NFE exome
AF:
0.122
Gnomad OTH exome
AF:
0.165
GnomAD4 exome
AF:
0.147
AC:
215412
AN:
1461490
Hom.:
17540
Cov.:
34
AF XY:
0.149
AC XY:
108288
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.342
Gnomad4 AMR exome
AF:
0.194
Gnomad4 ASJ exome
AF:
0.160
Gnomad4 EAS exome
AF:
0.185
Gnomad4 SAS exome
AF:
0.234
Gnomad4 FIN exome
AF:
0.172
Gnomad4 NFE exome
AF:
0.129
Gnomad4 OTH exome
AF:
0.163
GnomAD4 genome
AF:
0.196
AC:
29745
AN:
152126
Hom.:
3497
Cov.:
32
AF XY:
0.197
AC XY:
14666
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.324
Gnomad4 AMR
AF:
0.179
Gnomad4 ASJ
AF:
0.152
Gnomad4 EAS
AF:
0.201
Gnomad4 SAS
AF:
0.234
Gnomad4 FIN
AF:
0.178
Gnomad4 NFE
AF:
0.125
Gnomad4 OTH
AF:
0.185
Alfa
AF:
0.142
Hom.:
4327
Bravo
AF:
0.201
TwinsUK
AF:
0.141
AC:
521
ALSPAC
AF:
0.135
AC:
519
ESP6500AA
AF:
0.328
AC:
1444
ESP6500EA
AF:
0.126
AC:
1081
ExAC
AF:
0.172
AC:
20898
Asia WGS
AF:
0.265
AC:
924
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 16, 2007- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJul 22, 2016- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 25445213, 19863551, 27153395) -
Cardiomyopathy Benign:2
Benign, no assertion criteria providedclinical testingCohesion PhenomicsSep 23, 2022- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 15, 2018- -
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- -
Lethal acantholytic epidermolysis bullosa Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 13, 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 13, 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 GeneticsJun 25, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.82
T
MetaRNN
Benign
0.0042
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.066
Sift
Benign
0.076
T
Sift4G
Benign
0.18
T
Polyphen
0.0030
B
Vest4
0.090
MPC
0.27
ClinPred
0.0019
T
GERP RS
3.2
Varity_R
0.049
gMVP
0.33

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: rs6929069; hg19: chr6-7581636; COSMIC: COSV65791527; API