rs6929069

Positions:

• chr6-7581403-G-A

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1738G) has been classified as Uncertain significance.

• 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:18
• 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/exons	MANE	UniProt
DSP	NM_004415.4	c.5213G>A	p.Arg1738Gln	missense_variant	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3583-1239G>A		intron_variant
DSP	NM_001319034.2	c.4050+1163G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5213G>A	p.Arg1738Gln	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3583-1239G>A		intron_variant		1		A2
DSP	ENST00000710359.1	c.4050+1163G>A		intron_variant				A2

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:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 16, 2007	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25445213, 19863551, 27153395) -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 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
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
MutationTaster	Benign	1.0	P;P
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;