rs28763969

Positions:

chr6-7583652-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004415.4(DSP):c.6390T>C(p.Ala2130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,614,154 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 19 hom., cov: 31)

Exomes 𝑓: 0.014 ( 216 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.353

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 6-7583652-T-C is Benign according to our data. Variant chr6-7583652-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7583652-T-C is described in Lovd as [Benign]. Variant chr6-7583652-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.353 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00948 (1444/152264) while in subpopulation NFE AF= 0.0154 (1046/68024). AF 95% confidence interval is 0.0146. There are 19 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.6390T>C	p.Ala2130=	synonymous_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2 linkuse as main transcript	c.5061T>C	p.Ala1687=	synonymous_variant	24/24		NP_001305963.1
DSP	NM_001008844.3 linkuse as main transcript	c.4593T>C	p.Ala1531=	synonymous_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.6390T>C	p.Ala2130=	synonymous_variant	24/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.4593T>C	p.Ala1531=	synonymous_variant	24/24	1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.5061T>C	p.Ala1687=	synonymous_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00969

AC:

2435

AN:

251304

Hom.:

AF XY:

0.0104

AC XY:

1414

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.0145

AC:

21179

AN:

1461890

Hom.:

216

Cov.:

AF XY:

0.0145

AC XY:

10568

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.00503

Gnomad4 ASJ exome

AF:

0.00566

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.00406

Gnomad4 NFE exome

AF:

0.0167

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.00948

AC:

1444

AN:

152264

Hom.:

Cov.:

AF XY:

0.00954

AC XY:

710

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.00720

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00968

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2011	Ala2130Ala in exon 24 of DSP: This variant is classified as benign because it do es not change the amino acid and is frequent in the general population (dbSNP rs 28763969, MAF >1%). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DSP: BP4, BP7, BS1, BS2 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 14, 2018

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Woolly hair-skin fragility syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2015

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.7

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over