chr18-31031173-C-A

Variant names:

• chr18-31031173-C-A
• rs276936
• NM_001941.5:c.155-1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The ENST00000360428.9(DSC3):​c.155-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000184 in 1,606,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: DSC3 ENST00000360428.9 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 17 publications found

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]

DSC3 Gene-Disease associations (from GenCC):

• hereditary hypotrichosis with recurrent skin vesicles

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360428.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC3	NM_001941.5	MANE Select	c.155-1G>T		splice_acceptor intron	N/A	NP_001932.2
	DSC3	NM_024423.4		c.155-1G>T		splice_acceptor intron	N/A	NP_077741.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC3	ENST00000360428.9	TSL:1 MANE Select	c.155-1G>T		splice_acceptor intron	N/A	ENSP00000353608.4
	DSC3	ENST00000434452.5	TSL:5	c.155-1G>T		splice_acceptor intron	N/A	ENSP00000392068.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151804 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 288 AN: 1454486 Hom.: 0 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 723144

African (AFR) AF: 0.0000603 AC: 2 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000252 AC: 279 AN: 1108876

Other (OTH) AF: 0.0000999 AC: 6 AN: 60090

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151804 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74100

African (AFR) AF: 0.0000242 AC: 1 AN: 41286

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000644 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
PhyloP100		3.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs276936; hg19: chr18-28611139;