rs3848485

Variant names:

• chr18-31456353-A-G
• rs3848485
• NM_001944.3:c.49-87A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001944.3(DSG3):​c.49-87A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 864,172 control chromosomes in the GnomAD database, including 24,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6693 hom., cov: 32)
  • Exomes 𝑓: 0.22 (17891 hom.)
• Consequence: DSG3 NM_001944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0100
• Publications: 6 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-31456353-A-G is Benign according to our data. Variant chr18-31456353-A-G is described in ClinVar as [Benign]. Clinvar id is 1182152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG3	NM_001944.3	c.49-87A>G		intron_variant	Intron 1 of 15	ENST00000257189.5	NP_001935.2
DSG3	XM_011525850.3	c.49-87A>G		intron_variant	Intron 1 of 15		XP_011524152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG3	ENST00000257189.5	c.49-87A>G		intron_variant	Intron 1 of 15	1	NM_001944.3	ENSP00000257189.4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42267 AN: 151964 Hom.: 6663 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.216 AC: 153705 AN: 712090 Hom.: 17891 AF XY: 0.216 AC XY: 76399 AN XY: 353706

African (AFR) AF: 0.462 AC: 7236 AN: 15668

American (AMR) AF: 0.226 AC: 3842 AN: 17026

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 2489 AN: 12648

East Asian (EAS) AF: 0.154 AC: 4204 AN: 27380

South Asian (SAS) AF: 0.370 AC: 6609 AN: 17844

European-Finnish (FIN) AF: 0.266 AC: 10738 AN: 40324

Middle Eastern (MID) AF: 0.220 AC: 783 AN: 3566

European-Non Finnish (NFE) AF: 0.202 AC: 110595 AN: 546216

Other (OTH) AF: 0.229 AC: 7209 AN: 31418

GnomAD4 genome AF: 0.278 AC: 42354 AN: 152082 Hom.: 6693 Cov.: 32 AF XY: 0.281 AC XY: 20872 AN XY: 74358

African (AFR) AF: 0.444 AC: 18400 AN: 41446

American (AMR) AF: 0.201 AC: 3071 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3472

East Asian (EAS) AF: 0.154 AC: 796 AN: 5170

South Asian (SAS) AF: 0.361 AC: 1740 AN: 4826

European-Finnish (FIN) AF: 0.275 AC: 2899 AN: 10556

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14042 AN: 67998

Other (OTH) AF: 0.242 AC: 511 AN: 2114

Alfa AF: 0.260 Hom.: 952

Bravo AF: 0.277

Asia WGS AF: 0.243 AC: 846 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		0.010
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: rs3848485; hg19: chr18-29036316; COSMIC: COSV57129712;