rs113028223

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004415.4(DSP):c.423-16_423-15insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,613,606 control chromosomes in the GnomAD database, including 391 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 190 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 201 hom. )

Consequence

DSP
NM_004415.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.261

Publications

1 publications found

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]

DSP Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 8
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
keratosis palmoplantaris striata 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
skin fragility-woolly hair-palmoplantar keratoderma syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
lethal acantholytic epidermolysis bullosa
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
striate palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe dermatitis-multiple allergies-metabolic wasting syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 6-7559210-G-GC is Benign according to our data. Variant chr6-7559210-G-GC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 link	c.423-16_423-15insC	intron_variant	Intron 3 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.423-16_423-15insC		intron_variant	Intron 3 of 23	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

4254

AN:

152090

Hom.:

180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00800

AC:

1994

AN:

249314

AF XY:

0.00635

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00315

AC:

4607

AN:

1461398

Hom.:

201

Cov.:

AF XY:

0.00288

AC XY:

2093

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.101

AC:

3388

AN:

33450

American (AMR)

AF:

0.00550

AC:

246

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00486

AC:

419

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.000109

AC:

121

AN:

1111896

Other (OTH)

AF:

0.00683

AC:

412

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

228

457

685

914

1142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4291

AN:

152208

Hom.:

190

Cov.:

AF XY:

0.0277

AC XY:

2060

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0973

AC:

4040

AN:

41510

American (AMR)

AF:

0.0104

AC:

159

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00684

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68016

Other (OTH)

AF:

0.0204

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

201

402

603

804

1005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0319

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The DSP c.423-16_423-15insC variant involves the insetion of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1200/120544 control chromosomes (58 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1054381 (1047/9930). This frequency is about 4217 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over