rs1016835

Positions:

• chr6-7576294-G-A
• chr6-7576294-G-C
• chr6-7576294-G-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.2631G>A​(p.Arg877=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,944 control chromosomes in the GnomAD database, including 495,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43138 hom., cov: 32)
  • Exomes 𝑓: 0.79 (451999 hom.)
• Consequence: DSP NM_004415.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001223
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.269

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=-0.57).
• BP6: Variant 6-7576294-G-A is Benign according to our data. Variant chr6-7576294-G-A is described in ClinVar as [Benign]. Clinvar id is 44877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7576294-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24		NP_001305963.1
DSP	NM_001008844.3	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2631G>A	p.Arg877=	splice_region_variant, synonymous_variant	19/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113851 AN: 151938 Hom.: 43118 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.776

GnomAD3 exomes AF: 0.775 AC: 194456 AN: 251060 Hom.: 75519 AF XY: 0.777 AC XY: 105464 AN XY: 135730

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.803

Gnomad SAS exome AF: 0.741

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.786 AC: 1147720 AN: 1460886 Hom.: 451999 Cov.: 43 AF XY: 0.786 AC XY: 570968 AN XY: 726784

Gnomad4 AFR exome AF: 0.631

Gnomad4 AMR exome AF: 0.789

Gnomad4 ASJ exome AF: 0.815

Gnomad4 EAS exome AF: 0.812

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.783

GnomAD4 genome AF: 0.749 AC: 113923 AN: 152058 Hom.: 43138 Cov.: 32 AF XY: 0.748 AC XY: 55609 AN XY: 74324

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.825

Gnomad4 EAS AF: 0.798

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.798

Gnomad4 OTH AF: 0.771

Alfa AF: 0.795 Hom.: 116652

Bravo AF: 0.751

Asia WGS AF: 0.727 AC: 2526 AN: 3478

EpiCase AF: 0.818

EpiControl AF: 0.808

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Lethal acantholytic epidermolysis bullosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Woolly hair-skin fragility syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Keratosis palmoplantaris striata 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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	-0.57
CADD	Benign	5.7
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.030
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: rs1016835; hg19: chr6-7576527; COSMIC: COSV65794284;