18-30996906-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001941.5(DSC3):c.2378G>T(p.Arg793Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DSC3
NM_001941.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.246

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4141359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC3	NM_001941.5 linkuse as main transcript	c.2378G>T	p.Arg793Leu	missense_variant	15/16	ENST00000360428.9
DSC3	NM_024423.4 linkuse as main transcript	c.2378G>T	p.Arg793Leu	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC3	ENST00000360428.9 linkuse as main transcript	c.2378G>T	p.Arg793Leu	missense_variant	15/16	1	NM_001941.5	P1	Q14574-1
DSC3	ENST00000434452.5 linkuse as main transcript	c.2378G>T	p.Arg793Leu	missense_variant	15/17	5			Q14574-2
DSC3	ENST00000584980.1 linkuse as main transcript	c.503G>T	p.Arg168Leu	missense_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.2378G>T (p.R793L) alteration is located in exon 15 (coding exon 15) of the DSC3 gene. This alteration results from a G to T substitution at nucleotide position 2378, causing the arginine (R) at amino acid position 793 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0085

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Benign

0.88

DEOGEN2

Uncertain

0.61

D;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.095

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.46

P;P

Vest4

0.44

MutPred

0.42

Loss of solvent accessibility (P = 0.0022);Loss of solvent accessibility (P = 0.0022);

MVP

0.80

MPC

0.14

ClinPred

0.71

GERP RS

-1.8

Varity_R

0.14

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over