rs3778337

Positions:

• chr6-7565652-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004415.4(DSP):​c.939+132G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,247,782 control chromosomes in the GnomAD database, including 52,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.29 (46473 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 6-7565652-G-A is Benign according to our data. Variant chr6-7565652-G-A is described in ClinVar as [Benign]. Clinvar id is 672129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.939+132G>A		intron_variant		ENST00000379802.8
DSP	NM_001008844.3	c.939+132G>A		intron_variant
DSP	NM_001319034.2	c.939+132G>A		intron_variant
DSP	NM_001406591.1	c.939+132G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.939+132G>A		intron_variant		1	NM_004415.4	P2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40722 AN: 151956 Hom.: 5753 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.286 AC: 313046 AN: 1095708 Hom.: 46473 Cov.: 14 AF XY: 0.285 AC XY: 157051 AN XY: 551438

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.476

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.268 AC: 40741 AN: 152074 Hom.: 5759 Cov.: 32 AF XY: 0.266 AC XY: 19782 AN XY: 74348

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.459

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.288

Gnomad4 OTH AF: 0.264

Alfa AF: 0.283 Hom.: 3766

Bravo AF: 0.279

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.077
DANN	Benign	0.59

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: rs3778337; hg19: chr6-7565885;