Genetic Variant DSG3:c.217-145G>A (chr18-31458300-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001944.3(DSG3):c.217-145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 816,264 control chromosomes in the GnomAD database, including 1,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.069 ( 804 hom., cov: 32)

Exomes 𝑓: 0.022 ( 512 hom. )

Consequence

DSG3
NM_001944.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.646

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 18-31458300-G-A is Benign according to our data. Variant chr18-31458300-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288881.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 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.217-145G>A		intron	N/A	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.217-145G>A		intron	N/A	ENSP00000257189.4	P32926
	DSG3	ENST00000851332.1		c.49-2927G>A		intron	N/A	ENSP00000521391.1

Frequencies

GnomAD3 genomes

AF:

0.0686

AC:

10425

AN:

152052

Hom.:

802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0302

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.0531

GnomAD4 exome

AF:

0.0221

AC:

14672

AN:

664094

Hom.:

512

AF XY:

0.0209

AC XY:

7103

AN XY:

339216

show subpopulations

African (AFR)

AF:

0.200

AC:

3394

AN:

16966

American (AMR)

AF:

0.0214

AC:

462

AN:

21546

Ashkenazi Jewish (ASJ)

AF:

0.00349

AC:

AN:

14594

East Asian (EAS)

AF:

0.00

AC:

AN:

34474

South Asian (SAS)

AF:

0.00560

AC:

242

AN:

43214

European-Finnish (FIN)

AF:

0.0430

AC:

1836

AN:

42690

Middle Eastern (MID)

AF:

0.0430

AC:

AN:

2302

European-Non Finnish (NFE)

AF:

0.0168

AC:

7649

AN:

455256

Other (OTH)

AF:

0.0284

AC:

939

AN:

33052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

631

1261

1892

2522

3153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.0687

AC:

10452

AN:

152170

Hom.:

804

Cov.:

AF XY:

0.0669

AC XY:

4976

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.197

AC:

8155

AN:

41490

American (AMR)

AF:

0.0302

AC:

461

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00601

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0433

AC:

458

AN:

10572

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0177

AC:

1201

AN:

68024

Other (OTH)

AF:

0.0525

AC:

111

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

456

912

1368

1824

2280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0708

Hom.:

154

Bravo

AF:

0.0728

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.81

PhyloP100

-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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over