rs11558732

Positions:

• chr6-7585887-T-A

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.*9T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 1,612,636 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (69 hom.)
• Consequence: DSP NM_004415.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.08

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=-0.76).
• BP6: Variant 6-7585887-T-A is Benign according to our data. Variant chr6-7585887-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 44850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7585887-T-A is described in Lovd as [Benign]. Variant chr6-7585887-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0063 (959/152330) while in subpopulation NFE AF= 0.009 (612/68020). AF 95% confidence interval is 0.00841. There are 6 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.*9T>A		3_prime_UTR_variant	24/24	ENST00000379802.8
DSP	NM_001008844.3	c.*9T>A		3_prime_UTR_variant	24/24
DSP	NM_001319034.2	c.*9T>A		3_prime_UTR_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.*9T>A		3_prime_UTR_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.*9T>A		3_prime_UTR_variant	24/24	1		A2
DSP	ENST00000710359.1	c.*9T>A		3_prime_UTR_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152212 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00900

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00596 AC: 1485 AN: 248956 Hom.: 9 AF XY: 0.00572 AC XY: 772 AN XY: 134974

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00272

Gnomad FIN exome AF: 0.00596

Gnomad NFE exome AF: 0.00727

Gnomad OTH exome AF: 0.00985

GnomAD4 exome AF: 0.00818 AC: 11944 AN: 1460306 Hom.: 69 Cov.: 31 AF XY: 0.00795 AC XY: 5779 AN XY: 726536

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.00720

Gnomad4 NFE exome AF: 0.00894

Gnomad4 OTH exome AF: 0.00850

GnomAD4 genome AF: 0.00630 AC: 959 AN: 152330 Hom.: 6 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74498

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.00900

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00872 Hom.: 4

Bravo AF: 0.00620

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DSP: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 21723241, 26332594) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 20, 2012

*9T>A variant in 3' UTR of DSP: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and it has been ident ified in 1.11% (78/7020) of European American chromosomes by the NHLBI Exome Seq uencing Project in a broad population (http://evs.gs.washington.edu/EVS; rs11558 732). -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2015

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 05, 2015

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.6
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11558732; hg19: chr6-7586120;