Genetic Variant DSG3:p.Val115Val (chr18-31458573-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001944.3(DSG3):c.345C>T(p.Val115Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,613,462 control chromosomes in the GnomAD database, including 1,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 771 hom., cov: 32)

Exomes 𝑓: 0.021 ( 975 hom. )

Consequence

DSG3
NM_001944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.46

Publications

4 publications found

Variant links:

Genes affected

DSG3 (HGNC:3050): (desmoglein 3) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. The encoded protein has been identified as the autoantigen of the autoimmune blistering disease pemphigus vulgaris. [provided by RefSeq, Jan 2016]

DSG3 Gene-Disease associations (from GenCC):

blistering, acantholytic, of oral and laryngeal mucosa
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

DSG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 18-31458573-C-T is Benign according to our data. Variant chr18-31458573-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG3	NM_001944.3	MANE Select	c.345C>T	p.Val115Val	synonymous	Exon 4 of 16	NP_001935.2	P32926

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG3	ENST00000257189.5	TSL:1 MANE Select	c.345C>T	p.Val115Val	synonymous	Exon 4 of 16	ENSP00000257189.4	P32926
	DSG3	ENST00000851332.1		c.49-2654C>T		intron	N/A	ENSP00000521391.1

Frequencies

GnomAD3 genomes

AF:

0.0675

AC:

10266

AN:

152038

Hom.:

769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00623

Gnomad FIN

AF:

0.0435

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0176

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0299

AC:

7496

AN:

250868

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.201

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0450

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0214

AC:

31240

AN:

1461306

Hom.:

975

Cov.:

AF XY:

0.0203

AC XY:

14744

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.201

AC:

6711

AN:

33458

American (AMR)

AF:

0.0182

AC:

813

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

101

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00656

AC:

565

AN:

86150

European-Finnish (FIN)

AF:

0.0430

AC:

2297

AN:

53398

Middle Eastern (MID)

AF:

0.0515

AC:

297

AN:

5768

European-Non Finnish (NFE)

AF:

0.0169

AC:

18777

AN:

1111694

Other (OTH)

AF:

0.0278

AC:

1678

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1438

2876

4314

5752

7190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

786

1572

2358

3144

3930

<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:

0.0677

AC:

10294

AN:

152156

Hom.:

771

Cov.:

AF XY:

0.0659

AC XY:

4905

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.193

AC:

8007

AN:

41458

American (AMR)

AF:

0.0295

AC:

452

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00582

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0435

AC:

461

AN:

10598

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0176

AC:

1198

AN:

68010

Other (OTH)

AF:

0.0526

AC:

111

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

445

890

1334

1779

2224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0358

Hom.:

900

Bravo

AF:

0.0719

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0186

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

1.6

(source)

DANN

Benign

0.61

PhyloP100

-1.5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over