6-7575273-CT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_004415.4(DSP):c.2437-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 817,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00092 ( 3 hom., cov: 33)

Exomes 𝑓: 0.026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DSP
NM_004415.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.0620

Publications

0 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 -8 ACMG points.

BP6

Variant 6-7575273-CT-C is Benign according to our data. Variant chr6-7575273-CT-C is described in ClinVar as Benign. ClinVar VariationId is 163253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.2437-11delT	intron_variant	Intron 17 of 23	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.2437-11delT	intron_variant	Intron 17 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.2437-11delT	intron_variant	Intron 17 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.2437-21delT		intron_variant	Intron 17 of 23	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

121

AN:

147218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000951

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.00148

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000406

Gnomad OTH

AF:

0.000503

GnomAD2 exomes

AF:

0.0680

AC:

5778

AN:

84998

AF XY:

0.0687

show subpopulations

Gnomad AFR exome

AF:

0.0581

Gnomad AMR exome

AF:

0.0621

Gnomad ASJ exome

AF:

0.0557

Gnomad EAS exome

AF:

0.0572

Gnomad FIN exome

AF:

0.0528

Gnomad NFE exome

AF:

0.0757

Gnomad OTH exome

AF:

0.0588

GnomAD4 exome

AF:

0.0259

AC:

21176

AN:

817948

Hom.:

Cov.:

AF XY:

0.0260

AC XY:

10511

AN XY:

403684

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0321

AC:

584

AN:

18206

American (AMR)

AF:

0.0415

AC:

925

AN:

22266

Ashkenazi Jewish (ASJ)

AF:

0.0341

AC:

436

AN:

12800

East Asian (EAS)

AF:

0.0338

AC:

649

AN:

19174

South Asian (SAS)

AF:

0.0248

AC:

1097

AN:

44188

European-Finnish (FIN)

AF:

0.0344

AC:

946

AN:

27530

Middle Eastern (MID)

AF:

0.0211

AC:

AN:

3704

European-Non Finnish (NFE)

AF:

0.0243

AC:

15492

AN:

637162

Other (OTH)

AF:

0.0294

AC:

969

AN:

32918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.240

Heterozygous variant carriers

3702

7404

11106

14808

18510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

566

1132

1698

2264

2830

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000923

AC:

136

AN:

147288

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

71670

show subpopulations

African (AFR)

AF:

0.00196

AC:

AN:

40344

American (AMR)

AF:

0.000950

AC:

AN:

14734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

5096

South Asian (SAS)

AF:

0.000215

AC:

AN:

4658

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

9446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000406

AC:

AN:

66422

Other (OTH)

AF:

0.000499

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0682

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 20, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

2437-11delT in intron 17 of DSP: This variant is not expected to have clinical s ignificance because it has been identified in 18% (1498/8254) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS). -

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 2

Other:1

Institute of Human Genetics, University of Wuerzburg

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.062

Mutation Taster

=100/0

polymorphism

(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