rs61731476

chr6-7580153-G-Achr6-7580153-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004415.4(DSP):c.3963G>A(p.Gln1321=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0145 in 1,614,046 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (10 hom., cov: 32)
  • Exomes 𝑓: 0.015 (187 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.61

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 (BayesDel_noAF=-0.5).
• BP6: Variant 6-7580153-G-A is Benign according to our data. Variant chr6-7580153-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7580153-G-A is described in Lovd as [Benign]. Variant chr6-7580153-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0115 (1758/152240) while in subpopulation AMR AF= 0.0182 (278/15294). AF 95% confidence interval is 0.0164. There are 10 homozygotes in gnomad4. There are 843 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.3963G>A	p.Gln1321=	synonymous_variant	23/24	ENST00000379802.8
DSP	NM_001319034.2	c.3963G>A	p.Gln1321=	synonymous_variant	23/24
DSP	NM_001008844.3	c.3582+381G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3963G>A	p.Gln1321=	synonymous_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+381G>A		intron_variant		1		A2
DSP	ENST00000710359.1	c.3963G>A	p.Gln1321=	synonymous_variant	23/24			A2

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1758 AN: 152124 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0129 AC: 3227 AN: 250704 Hom.: 33 AF XY: 0.0133 AC XY: 1798 AN XY: 135598

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00975

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00834

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0149 AC: 21720 AN: 1461806 Hom.: 187 Cov.: 32 AF XY: 0.0146 AC XY: 10598 AN XY: 727204

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00915

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00940

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0115 AC: 1758 AN: 152240 Hom.: 10 Cov.: 32 AF XY: 0.0113 AC XY: 843 AN XY: 74430

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0152 Hom.: 10

Bravo AF: 0.0112

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2016	p.Gln1321Gln in exon 23 of DSP: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1.9% (1272/66208) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org;dbSNP rs61731476). -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -

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

Likely 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 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

Jul 30, 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	-0.50
Cadd	Benign	6.3
Dann	Benign	0.95

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: rs61731476; hg19: chr6-7580386;