rs2076303

Positions:

• chr6-7571793-T-A
• chr6-7571793-T-C
• chr6-7571793-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.1904-49T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,583,700 control chromosomes in the GnomAD database, including 150,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14099 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136094 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.222

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-7571793-T-A is Benign according to our data. Variant chr6-7571793-T-A is described in ClinVar as [Benign]. Clinvar id is 259382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571793-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1904-49T>A		intron_variant		ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1904-49T>A		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.1904-49T>A		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1904-49T>A		intron_variant		1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1904-49T>A		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1904-49T>A		intron_variant				ENSP00000518230.1
DSP	ENST00000684395.1	n.496T>A		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63797 AN: 151920 Hom.: 14095 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.422

GnomAD3 exomes AF: 0.462 AC: 112461 AN: 243280 Hom.: 27770 AF XY: 0.458 AC XY: 60539 AN XY: 132304

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.763

Gnomad SAS exome AF: 0.490

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.428 AC: 613045 AN: 1431662 Hom.: 136094 Cov.: 29 AF XY: 0.430 AC XY: 306946 AN XY: 714076

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.569

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.797

Gnomad4 SAS exome AF: 0.486

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.420 AC: 63829 AN: 152038 Hom.: 14099 Cov.: 32 AF XY: 0.425 AC XY: 31550 AN XY: 74302

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.767

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.422

Alfa AF: 0.403 Hom.: 2328

Bravo AF: 0.436

Asia WGS AF: 0.550 AC: 1910 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Woolly hair-skin fragility syndrome 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

Jun 15, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Keratosis palmoplantaris striata 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.38
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: rs2076303; hg19: chr6-7572026; COSMIC: COSV65791877;