6-7567737-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004415.4(DSP):c.1141-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,611,848 control chromosomes in the GnomAD database, including 471,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 45824 hom., cov: 31)

Exomes 𝑓: 0.76 ( 425533 hom. )

Consequence

DSP
NM_004415.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0290

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-7567737-C-T is Benign according to our data. Variant chr6-7567737-C-T is described in ClinVar as Benign. ClinVar VariationId is 259381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DSP	NM_004415.4 link	c.1141-44C>T	intron_variant	Intron 9 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2 link	c.1141-44C>T	intron_variant	Intron 9 of 23		NP_001305963.1
DSP	NM_001008844.3 link	c.1141-44C>T	intron_variant	Intron 9 of 23		NP_001008844.1
DSP	NM_001406591.1 link	c.1141-44C>T	intron_variant	Intron 9 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.1141-44C>T		intron_variant	Intron 9 of 23	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes

AF:

0.775

AC:

117801

AN:

151956

Hom.:

45804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.797

Gnomad AMI

AF:

0.784

Gnomad AMR

AF:

0.781

Gnomad ASJ

AF:

0.843

Gnomad EAS

AF:

0.813

Gnomad SAS

AF:

0.686

Gnomad FIN

AF:

0.717

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.769

Gnomad OTH

AF:

0.779

GnomAD2 exomes

AF:

0.760

AC:

190311

AN:

250490

AF XY:

0.756

show subpopulations

Gnomad AFR exome

AF:

0.800

Gnomad AMR exome

AF:

0.767

Gnomad ASJ exome

AF:

0.835

Gnomad EAS exome

AF:

0.805

Gnomad FIN exome

AF:

0.714

Gnomad NFE exome

AF:

0.767

Gnomad OTH exome

AF:

0.769

GnomAD4 exome

AF:

0.763

AC:

1113092

AN:

1459774

Hom.:

425533

Cov.:

AF XY:

0.761

AC XY:

552552

AN XY:

726266

show subpopulations

African (AFR)

AF:

0.797

AC:

26650

AN:

33450

American (AMR)

AF:

0.772

AC:

34511

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.834

AC:

21785

AN:

26110

East Asian (EAS)

AF:

0.834

AC:

33078

AN:

39660

South Asian (SAS)

AF:

0.684

AC:

58745

AN:

85886

European-Finnish (FIN)

AF:

0.713

AC:

37793

AN:

53034

Middle Eastern (MID)

AF:

0.778

AC:

4480

AN:

5760

European-Non Finnish (NFE)

AF:

0.765

AC:

849394

AN:

1110846

Other (OTH)

AF:

0.773

AC:

46656

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

13183

26366

39549

52732

65915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20424

40848

61272

81696

102120

<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:

0.775

AC:

117866

AN:

152074

Hom.:

45824

Cov.:

AF XY:

0.773

AC XY:

57405

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.797

AC:

33050

AN:

41478

American (AMR)

AF:

0.781

AC:

11946

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.843

AC:

2928

AN:

3472

East Asian (EAS)

AF:

0.812

AC:

4186

AN:

5154

South Asian (SAS)

AF:

0.686

AC:

3310

AN:

4822

European-Finnish (FIN)

AF:

0.717

AC:

7562

AN:

10554

Middle Eastern (MID)

AF:

0.813

AC:

239

AN:

294

European-Non Finnish (NFE)

AF:

0.769

AC:

52294

AN:

67990

Other (OTH)

AF:

0.775

AC:

1636

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1351

2702

4053

5404

6755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.770

Hom.:

9839

Bravo

AF:

0.786

Asia WGS

AF:

0.699

AC:

2431

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Woolly hair-skin fragility syndrome

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Keratosis palmoplantaris striata 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.9

(source)

DANN

Benign

0.43

PhyloP100

-0.029

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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