6-7578586-T-G

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.3084+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,576,868 control chromosomes in the GnomAD database, including 485,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43290 hom., cov: 31)

Exomes 𝑓: 0.79 ( 442428 hom. )

Consequence

DSP
NM_004415.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0270

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=-0.84).

BP6

Variant 6-7578586-T-G is Benign according to our data. Variant chr6-7578586-T-G is described in ClinVar as Benign. ClinVar VariationId is 259383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.3084+24T>G	intron_variant	Intron 22 of 23	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.3084+24T>G	intron_variant	Intron 22 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3084+24T>G	intron_variant	Intron 22 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.3084+24T>G		intron_variant	Intron 22 of 23	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.752

AC:

113963

AN:

151468

Hom.:

43271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.656

Gnomad AMI

AF:

0.863

Gnomad AMR

AF:

0.797

Gnomad ASJ

AF:

0.824

Gnomad EAS

AF:

0.797

Gnomad SAS

AF:

0.748

Gnomad FIN

AF:

0.715

Gnomad MID

AF:

0.815

Gnomad NFE

AF:

0.797

Gnomad OTH

AF:

0.780

GnomAD2 exomes

AF:

0.776

AC:

193921

AN:

249964

AF XY:

0.778

show subpopulations

Gnomad AFR exome

AF:

0.654

Gnomad AMR exome

AF:

0.786

Gnomad ASJ exome

AF:

0.817

Gnomad EAS exome

AF:

0.803

Gnomad FIN exome

AF:

0.720

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.785

GnomAD4 exome

AF:

0.787

AC:

1121668

AN:

1425284

Hom.:

442428

Cov.:

AF XY:

0.787

AC XY:

559805

AN XY:

711420

show subpopulations

African (AFR)

AF:

0.644

AC:

20981

AN:

32566

American (AMR)

AF:

0.791

AC:

35187

AN:

44478

Ashkenazi Jewish (ASJ)

AF:

0.814

AC:

21064

AN:

25864

East Asian (EAS)

AF:

0.813

AC:

32038

AN:

39420

South Asian (SAS)

AF:

0.747

AC:

63672

AN:

85198

European-Finnish (FIN)

AF:

0.720

AC:

38242

AN:

53086

Middle Eastern (MID)

AF:

0.797

AC:

4539

AN:

5696

European-Non Finnish (NFE)

AF:

0.796

AC:

859548

AN:

1079856

Other (OTH)

AF:

0.785

AC:

46397

AN:

59120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

10563

21126

31689

42252

52815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19912

39824

59736

79648

99560

<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:

0.752

AC:

114033

AN:

151584

Hom.:

43290

Cov.:

AF XY:

0.751

AC XY:

55630

AN XY:

74082

show subpopulations

African (AFR)

AF:

0.656

AC:

27115

AN:

41322

American (AMR)

AF:

0.797

AC:

12128

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

2855

AN:

3464

East Asian (EAS)

AF:

0.797

AC:

4107

AN:

5154

South Asian (SAS)

AF:

0.749

AC:

3611

AN:

4824

European-Finnish (FIN)

AF:

0.715

AC:

7491

AN:

10480

Middle Eastern (MID)

AF:

0.829

AC:

242

AN:

292

European-Non Finnish (NFE)

AF:

0.797

AC:

54071

AN:

67818

Other (OTH)

AF:

0.775

AC:

1633

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1392

2784

4176

5568

6960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.772

Hom.:

8509

Bravo

AF:

0.756

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 15, 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

-0.84

CADD

Benign

3.2

(source)

DANN

Benign

0.50

PhyloP100

-0.027

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