rs11558731

Variant names:

• chr6-7585437-C-A
• rs11558731
• NM_004415.4:c.8175C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7585437-C-A
• chr6-7585437-C-G
• chr6-7585437-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):​c.8175C>A​(p.Arg2725Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0561 in 1,614,098 control chromosomes in the GnomAD database, including 2,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (207 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2674 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.876

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-7585437-C-A is Benign according to our data. Variant chr6-7585437-C-A is described in ClinVar as [Benign]. Clinvar id is 44961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7585437-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.8175C>A	p.Arg2725Arg	synonymous_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6846C>A	p.Arg2282Arg	synonymous_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.6378C>A	p.Arg2126Arg	synonymous_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8175C>A	p.Arg2725Arg	synonymous_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.6378C>A	p.Arg2126Arg	synonymous_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.6846C>A	p.Arg2282Arg	synonymous_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6556 AN: 152094 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0504

GnomAD3 exomes AF: 0.0460 AC: 11573 AN: 251438 Hom.: 370 AF XY: 0.0465 AC XY: 6320 AN XY: 135916

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0673

Gnomad OTH exome AF: 0.0538

GnomAD4 exome AF: 0.0575 AC: 84054 AN: 1461886 Hom.: 2674 Cov.: 38 AF XY: 0.0567 AC XY: 41252 AN XY: 727244

Gnomad4 AFR exome AF: 0.00896

Gnomad4 AMR exome AF: 0.0372

Gnomad4 ASJ exome AF: 0.0662

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0656

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0430 AC: 6551 AN: 152212 Hom.: 207 Cov.: 32 AF XY: 0.0430 AC XY: 3203 AN XY: 74428

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0490

Gnomad4 ASJ AF: 0.0698

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0457

Gnomad4 NFE AF: 0.0647

Gnomad4 OTH AF: 0.0494

Alfa AF: 0.0563 Hom.: 121

Bravo AF: 0.0428

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0670

EpiControl AF: 0.0681

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg2725Arg in exon 24 of DSP: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It it has been identified in 6.5% (453/7020) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS/dbSNP rs11558731). -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Apr 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Benign:1

Jun 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.47
CADD	Benign	9.5
DANN	Benign	0.84
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

Other links and lift over

dbSNP: rs11558731; hg19: chr6-7585670; COSMIC: COSV60940795; COSMIC: COSV60940795;