18-30994506-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001941.5(DSC3):c.2494-134C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 1,577,370 control chromosomes in the GnomAD database, including 13,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5176 hom., cov: 32)
  • Exomes 𝑓: 0.080 (8221 hom.)
• Consequence: DSC3 NM_001941.5 intron
• Scores: Splicing: ADA: 0.0001368
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.07

Genes affected

DSC3 (HGNC:3037): (desmocollin 3) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Mutations in this gene are a cause of hypotrichosis and recurrent skin vesicles disorder. The protein can act as an autoantigen in pemphigus diseases, and it is also considered to be a biomarker for some cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 18-30994506-G-A is Benign according to our data. Variant chr18-30994506-G-A is described in ClinVar as [Benign]. Clinvar id is 1276898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC3	NM_001941.5	c.2494-134C>T		intron_variant		ENST00000360428.9
DSC3	NM_024423.4	c.2494-10C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC3	ENST00000360428.9	c.2494-134C>T		intron_variant		1	NM_001941.5	P1
DSC3	ENST00000434452.5	c.2494-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5
DSC3	ENST00000584980.1	c.618-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29412 AN: 151994 Hom.: 5160 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.125 AC: 31335 AN: 250608 Hom.: 3540 AF XY: 0.117 AC XY: 15912 AN XY: 135504

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0801 AC: 114225 AN: 1425258 Hom.: 8221 Cov.: 28 AF XY: 0.0813 AC XY: 57749 AN XY: 710246

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0241

Gnomad4 NFE exome AF: 0.0591

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.194 AC: 29475 AN: 152112 Hom.: 5176 Cov.: 32 AF XY: 0.189 AC XY: 14022 AN XY: 74380

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.175

Alfa AF: 0.120 Hom.: 1370

Bravo AF: 0.220

Asia WGS AF: 0.161 AC: 560 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

DSC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.11		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: rs8089682; hg19: chr18-28574472;