NM_001941.5:c.474+271A>G

Variant names:

• chr18-31029238-T-C
• rs276942
• NM_001941.5:c.474+271A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001941.5(DSC3):​c.474+271A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,968 control chromosomes in the GnomAD database, including 17,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (17137 hom., cov: 32)
• Consequence: DSC3 NM_001941.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.01
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 18-31029238-T-C is Benign according to our data. Variant chr18-31029238-T-C is described in ClinVar as Benign. ClinVar VariationId is 1288248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5	c.474+271A>G		intron_variant	Intron 4 of 15	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.474+271A>G		intron_variant	Intron 4 of 16		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.474+271A>G		intron_variant	Intron 4 of 15	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.474+271A>G		intron_variant	Intron 4 of 16	5		ENSP00000392068.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70813 AN: 151850 Hom.: 17137 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.454

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

GnomAD4 genome AF: 0.466 AC: 70850 AN: 151968 Hom.: 17137 Cov.: 32 AF XY: 0.476 AC XY: 35353 AN XY: 74262

African (AFR) AF: 0.450 AC: 18643 AN: 41458

American (AMR) AF: 0.495 AC: 7559 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3466

East Asian (EAS) AF: 0.883 AC: 4548 AN: 5152

South Asian (SAS) AF: 0.643 AC: 3099 AN: 4818

European-Finnish (FIN) AF: 0.505 AC: 5340 AN: 10566

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.426 AC: 28918 AN: 67928

Other (OTH) AF: 0.452 AC: 953 AN: 2108

Alfa AF: 0.437 Hom.: 45582

Bravo AF: 0.461

Asia WGS AF: 0.692 AC: 2405 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.31
PhyloP100		-2.0
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: rs276942; hg19: chr18-28609204; COSMIC: COSV64575502;