rs11558732

Variant names:

• chr6-7585887-T-A
• rs11558732
• NM_004415.4:c.*9T>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:14
• 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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.*9T>A		3_prime_UTR_variant	Exon 24 of 24			ENSP00000518230.1

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21723241, 26332594) -

Sep 16, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSP: BS1, BS2 -

not specified Benign:2

Jan 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

*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). -

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 18, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Jun 05, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Mar 26, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 26, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 26, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;