rs28763962

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.1903+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,026 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 151 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 138 hom. )

Consequence

DSP
NM_004415.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00009522
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.291
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 (BayesDel_noAF=-0.85).
BP6
Variant 6-7571591-T-C is Benign according to our data. Variant chr6-7571591-T-C is described in ClinVar as [Benign]. Clinvar id is 36019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571591-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant 1 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.1903+7T>C splice_region_variant, intron_variant ENSP00000518230.1
DSPENST00000684395.1 linkuse as main transcriptn.294T>C non_coding_transcript_exon_variant 2/5

Frequencies

GnomAD3 genomes
AF:
0.0238
AC:
3626
AN:
152172
Hom.:
150
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0830
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00903
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.0148
GnomAD3 exomes
AF:
0.00602
AC:
1509
AN:
250776
Hom.:
65
AF XY:
0.00431
AC XY:
584
AN XY:
135564
show subpopulations
Gnomad AFR exome
AF:
0.0823
Gnomad AMR exome
AF:
0.00396
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.00248
AC:
3618
AN:
1461736
Hom.:
138
Cov.:
32
AF XY:
0.00219
AC XY:
1594
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.0872
Gnomad4 AMR exome
AF:
0.00432
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000127
Gnomad4 OTH exome
AF:
0.00558
GnomAD4 genome
AF:
0.0239
AC:
3645
AN:
152290
Hom.:
151
Cov.:
32
AF XY:
0.0229
AC XY:
1702
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0832
Gnomad4 AMR
AF:
0.00902
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.0147
Alfa
AF:
0.0107
Hom.:
30
Bravo
AF:
0.0270
Asia WGS
AF:
0.00491
AC:
17
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 29, 2012This 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, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 09, 2011- -
not provided Benign:2
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 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 submittercurationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.22
DANN
Benign
0.61
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000095
dbscSNV1_RF
Benign
0.0040
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: rs28763962; hg19: chr6-7571824; API