6-7585371-AAAG-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PM4_SupportingBP6_Very_StrongBS1

The NM_004415.4(DSP):c.8117_8119delAGA(p.Lys2706del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00015 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DSP
NM_004415.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 5.13

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 -11 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004415.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 6-7585371-AAAG-A is Benign according to our data. Variant chr6-7585371-AAAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000153 (223/1461812) while in subpopulation AMR AF = 0.00402 (180/44724). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAdExome4. There are 83 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.8117_8119delAGA	p.Lys2706del	disruptive_inframe_deletion	Exon 24 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.6788_6790delAGA	p.Lys2263del	disruptive_inframe_deletion	Exon 24 of 24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.6320_6322delAGA	p.Lys2107del	disruptive_inframe_deletion	Exon 24 of 24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.8117_8119delAGA	p.Lys2706del	disruptive_inframe_deletion	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000601

AC:

151

AN:

251426

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00419

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461812

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.00402

AC:

180

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111946

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000125

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41546

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.0000339

Hom.:

Bravo

AF:

0.000336

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Apr 23, 2018

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DSP c.8117_8119delAGA (p.Lys2706del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00057 in 277174 control chromosomes. The observed variant frequency is approximately 57 fold above the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8117_8119delAGA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014: one VUS, one likely benign, and one benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 30, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Nov 30, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:2

Jun 26, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 16, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 29, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DSP-related disorder

Benign:1

Nov 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=71/29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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