NM_001941.5:c.1664-180G>C

Variant names:

• chr18-31007311-C-G
• rs12607476
• NM_001941.5:c.1664-180G>C

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.1664-180G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,002 control chromosomes in the GnomAD database, including 5,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (5529 hom., cov: 32)
• Consequence: DSC3 NM_001941.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 18-31007311-C-G is Benign according to our data. Variant chr18-31007311-C-G is described in ClinVar as [Benign]. Clinvar id is 1267666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5	c.1664-180G>C		intron_variant	Intron 11 of 15	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.1664-180G>C		intron_variant	Intron 11 of 16		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.1664-180G>C		intron_variant	Intron 11 of 15	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.1664-180G>C		intron_variant	Intron 11 of 16	5		ENSP00000392068.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39211 AN: 151886 Hom.: 5522 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.147

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.258 AC: 39239 AN: 152002 Hom.: 5529 Cov.: 32 AF XY: 0.264 AC XY: 19622 AN XY: 74260

African (AFR) AF: 0.252 AC: 10460 AN: 41462

American (AMR) AF: 0.183 AC: 2787 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 699 AN: 3468

East Asian (EAS) AF: 0.588 AC: 3037 AN: 5162

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4820

European-Finnish (FIN) AF: 0.330 AC: 3488 AN: 10554

Middle Eastern (MID) AF: 0.148 AC: 43 AN: 290

European-Non Finnish (NFE) AF: 0.240 AC: 16332 AN: 67964

Other (OTH) AF: 0.238 AC: 501 AN: 2106

Alfa AF: 0.237 Hom.: 547

Bravo AF: 0.245

Asia WGS AF: 0.416 AC: 1444 AN: 3468

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.084
DANN	Benign	0.27
PhyloP100		-1.5
PromoterAI		0.0070	Neutral
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: rs12607476; hg19: chr18-28587277;