18-31001476-T-C

Position:

• chr18-31001476-T-C

Variant summary

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

The NM_001941.5(DSC3):​c.2235+142A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 930,174 control chromosomes in the GnomAD database, including 33,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5170 hom., cov: 32)
  • Exomes 𝑓: 0.26 (28794 hom.)
• Consequence: DSC3 NM_001941.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.246

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-31001476-T-C is Benign according to our data. Variant chr18-31001476-T-C is described in ClinVar as [Benign]. Clinvar id is 1290685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC3	NM_001941.5	c.2235+142A>G		intron_variant		ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.2235+142A>G		intron_variant			NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.2235+142A>G		intron_variant		1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.2235+142A>G		intron_variant		5		ENSP00000392068.1
DSC3	ENST00000584980.1	c.357+142A>G		intron_variant		5		ENSP00000464283.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37951 AN: 151744 Hom.: 5170 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.259 AC: 201368 AN: 778312 Hom.: 28794 AF XY: 0.261 AC XY: 104030 AN XY: 398980

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.571

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.250 AC: 37965 AN: 151862 Hom.: 5170 Cov.: 32 AF XY: 0.255 AC XY: 18927 AN XY: 74210

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.230

Alfa AF: 0.123 Hom.: 207

Bravo AF: 0.236

Asia WGS AF: 0.409 AC: 1411 AN: 3450

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.55

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: rs1313579; hg19: chr18-28581442;