rs12455894

Variant names:

• chr18-31039829-G-A
• rs12455894
• NM_001941.5:c.69+2763C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001941.5(DSC3):​c.69+2763C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0947 in 152,104 control chromosomes in the GnomAD database, including 783 homozygotes. 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 0.095 (783 hom., cov: 33)
• Consequence: DSC3 NM_001941.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5	c.69+2763C>T		intron_variant	Intron 1 of 15	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.69+2763C>T		intron_variant	Intron 1 of 16		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.69+2763C>T		intron_variant	Intron 1 of 15	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.69+2763C>T		intron_variant	Intron 1 of 16	5		ENSP00000392068.1

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14389 AN: 151986 Hom.: 783 Cov.: 33

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0758

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0947 AC: 14403 AN: 152104 Hom.: 783 Cov.: 33 AF XY: 0.0961 AC XY: 7149 AN XY: 74356

African (AFR) AF: 0.0614 AC: 2550 AN: 41504

American (AMR) AF: 0.104 AC: 1595 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0730 AC: 253 AN: 3466

East Asian (EAS) AF: 0.0629 AC: 326 AN: 5180

South Asian (SAS) AF: 0.0553 AC: 266 AN: 4808

European-Finnish (FIN) AF: 0.154 AC: 1631 AN: 10572

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7549 AN: 67986

Other (OTH) AF: 0.0774 AC: 163 AN: 2106

Alfa AF: 0.103 Hom.: 1156

Bravo AF: 0.0880

Asia WGS AF: 0.0880 AC: 307 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.63
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12455894; hg19: chr18-28619795;