rs6929069

Variant names:

• chr6-7581403-G-A
• rs6929069
• NM_004415.4:c.5213G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7581403-G-A
• chr6-7581403-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.5213G>A​(p.Arg1738Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,616 control chromosomes in the GnomAD database, including 21,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3497 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17540 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.629

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004233688).
• BP6: Variant 6-7581403-G-A is Benign according to our data. Variant chr6-7581403-G-A is described in ClinVar as [Benign]. Clinvar id is 44925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7581403-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.5213G>A	p.Arg1738Gln	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+1163G>A		intron_variant	Intron 23 of 23		NP_001305963.1
DSP	NM_001008844.3	c.3583-1239G>A		intron_variant	Intron 23 of 23		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5213G>A	p.Arg1738Gln	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3583-1239G>A		intron_variant	Intron 23 of 23	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4050+1163G>A		intron_variant	Intron 23 of 23			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29704 AN: 152008 Hom.: 3491 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.172 AC: 43268 AN: 251186 Hom.: 4162 AF XY: 0.170 AC XY: 23120 AN XY: 135812

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.147 AC: 215412 AN: 1461490 Hom.: 17540 Cov.: 34 AF XY: 0.149 AC XY: 108288 AN XY: 727086

Gnomad4 AFR exome AF: 0.342

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.196 AC: 29745 AN: 152126 Hom.: 3497 Cov.: 32 AF XY: 0.197 AC XY: 14666 AN XY: 74374

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.185

Alfa AF: 0.142 Hom.: 4327

Bravo AF: 0.201

TwinsUK AF: 0.141 AC: 521

ALSPAC AF: 0.135 AC: 519

ESP6500AA AF: 0.328 AC: 1444

ESP6500EA AF: 0.126 AC: 1081

ExAC AF: 0.172 AC: 20898

Asia WGS AF: 0.265 AC: 924 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 16, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not provided Benign:3

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25445213, 19863551, 27153395) -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance: 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

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. -

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 25, 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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.066
Sift	Benign	0.076	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.090
MPC		0.27
ClinPred		0.0019	T
GERP RS		3.2
Varity_R		0.049
gMVP		0.33

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: rs6929069; hg19: chr6-7581636; COSMIC: COSV65791527;