chr18-31032263-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001941.5(DSC3):c.83C>A(p.Ala28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,609,726 control chromosomes in the GnomAD database, including 3,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 245 hom., cov: 32)

Exomes 𝑓: 0.058 ( 2949 hom. )

Consequence

DSC3
NM_001941.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.91

Publications

20 publications found

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 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)

DSC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002650261).

BP6

Variant 18-31032263-G-T is Benign according to our data. Variant chr18-31032263-G-T is described in ClinVar as Benign. ClinVar VariationId is 1268029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5 link	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 16	ENST00000360428.9	NP_001932.2	Q14574-1
DSC3	NM_024423.4 link	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 17		NP_077741.2	Q14574-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9 link	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 16	1	NM_001941.5	ENSP00000353608.4		Q14574-1
DSC3	ENST00000434452.5 link	c.83C>A	p.Ala28Asp	missense_variant	Exon 2 of 17	5		ENSP00000392068.1		Q14574-2

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

7139

AN:

151950

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.0386

Gnomad SAS

AF:

0.0289

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0642

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0509

AC:

12780

AN:

251018

AF XY:

0.0516

show subpopulations

Gnomad AFR exome

AF:

0.00902

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.0296

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0645

Gnomad OTH exome

AF:

0.0485

GnomAD4 exome

AF:

0.0580

AC:

84612

AN:

1457658

Hom.:

2949

Cov.:

AF XY:

0.0573

AC XY:

41583

AN XY:

725380

show subpopulations

African (AFR)

AF:

0.00816

AC:

273

AN:

33450

American (AMR)

AF:

0.0248

AC:

1107

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

323

AN:

26120

East Asian (EAS)

AF:

0.0404

AC:

1602

AN:

39624

South Asian (SAS)

AF:

0.0275

AC:

2373

AN:

86200

European-Finnish (FIN)

AF:

0.125

AC:

6677

AN:

53394

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0626

AC:

69328

AN:

1108104

Other (OTH)

AF:

0.0472

AC:

2848

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

3567

7135

10702

14270

17837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2476

4952

7428

9904

12380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0469

AC:

7139

AN:

152068

Hom.:

245

Cov.:

AF XY:

0.0498

AC XY:

3701

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0110

AC:

458

AN:

41488

American (AMR)

AF:

0.0306

AC:

467

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3470

East Asian (EAS)

AF:

0.0385

AC:

199

AN:

5172

South Asian (SAS)

AF:

0.0289

AC:

139

AN:

4814

European-Finnish (FIN)

AF:

0.127

AC:

1343

AN:

10540

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0642

AC:

4367

AN:

67994

Other (OTH)

AF:

0.0313

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

346

691

1037

1382

1728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0551

Hom.:

1348

Bravo

AF:

0.0364

TwinsUK

AF:

0.0715

AC:

265

ALSPAC

AF:

0.0643

AC:

248

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.0587

AC:

505

ExAC

AF:

0.0514

AC:

6237

Asia WGS

AF:

0.0440

AC:

153

AN:

3476

EpiCase

AF:

0.0522

EpiControl

AF:

0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

T;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.089

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.46

P;P

Vest4

0.18

MPC

0.19

ClinPred

0.024

GERP RS

3.5

Varity_R

0.14

gMVP

0.65

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over