6-7542041-T-C

Position:

• chr6-7542041-T-C

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.126T>C​(p.Tyr42=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,575,704 control chromosomes in the GnomAD database, including 2,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (425 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2333 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.70

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]

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-7542041-T-C is Benign according to our data. Variant chr6-7542041-T-C is described in ClinVar as [Benign]. Clinvar id is 44855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7542041-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.126T>C	p.Tyr42=	synonymous_variant	1/24	ENST00000379802.8
DSP-AS1	NR_183331.1	n.39-988A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.126T>C	p.Tyr42=	synonymous_variant	1/24	1	NM_004415.4	P2
DSP-AS1	ENST00000690863.2	n.344+730A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0678 AC: 10307 AN: 151964 Hom.: 418 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0680

GnomAD3 exomes AF: 0.0546 AC: 9906 AN: 181368 Hom.: 325 AF XY: 0.0550 AC XY: 5378 AN XY: 97866

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0166

Gnomad SAS exome AF: 0.0497

Gnomad FIN exome AF: 0.0605

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0558 AC: 79432 AN: 1423620 Hom.: 2333 Cov.: 32 AF XY: 0.0556 AC XY: 39164 AN XY: 704802

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0359

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0417

Gnomad4 SAS exome AF: 0.0496

Gnomad4 FIN exome AF: 0.0613

Gnomad4 NFE exome AF: 0.0539

Gnomad4 OTH exome AF: 0.0638

GnomAD4 genome AF: 0.0680 AC: 10344 AN: 152084 Hom.: 425 Cov.: 33 AF XY: 0.0674 AC XY: 5013 AN XY: 74382

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0471

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.0434

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0597 Hom.: 352

Bravo AF: 0.0696

Asia WGS AF: 0.0460 AC: 160 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2012	Tyr42Tyr in exon 1 of DSP: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 5% (349/6940) of European American chromosomes and 9% (334/3356) of African American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs36087964) -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 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	-0.73
CADD	Benign	12
DANN	Benign	0.74

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: rs36087964; hg19: chr6-7542274;