rs28763968

Positions:

• chr6-7580963-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004415.4(DSP):​c.4773G>A​(p.Arg1591Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,084 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.017 (255 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 2.12

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=-0.49).
• BP6: Variant 6-7580963-G-A is Benign according to our data. Variant chr6-7580963-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7580963-G-A is described in Lovd as [Benign]. Variant chr6-7580963-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1989/152308) while in subpopulation NFE AF= 0.018 (1223/68014). AF 95% confidence interval is 0.0171. There are 17 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.4773G>A	p.Arg1591Arg	synonymous_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+723G>A		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.3582+1191G>A		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4773G>A	p.Arg1591Arg	synonymous_variant	23/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3582+1191G>A		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4050+723G>A		intron_variant				ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152190 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0138 AC: 3458 AN: 250108 Hom.: 39 AF XY: 0.0135 AC XY: 1836 AN XY: 135536

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0171 AC: 25017 AN: 1461776 Hom.: 255 Cov.: 32 AF XY: 0.0166 AC XY: 12056 AN XY: 727170

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0131 AC: 1989 AN: 152308 Hom.: 17 Cov.: 32 AF XY: 0.0135 AC XY: 1002 AN XY: 74476

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0152 Hom.: 10

Bravo AF: 0.0122

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0174

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2011	Arg1591Arg in exon 23 of DSP: This variant has been reported in the SNP database (rs28763968) and is present in 1.8% (127/7020) of Caucasian chromosomes in a br oad clinical cohort from the NHLBI Exome sequencing project (http://evs.gs.washi ngton.edu/EVS/). It does not change an amino acid and does not affect the splice consensus sequence. This makes a disease causing role very unlikely. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2014	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

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

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

May 06, 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	-0.49
CADD	Benign	9.0
DANN	Benign	0.63

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: rs28763968; hg19: chr6-7581196;