18-31459042-C-G

Variant names:

• chr18-31459042-C-G
• rs771333335
• NM_001944.3:c.382C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001944.3(DSG3):​c.382C>G​(p.Arg128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,000 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSG3 NM_001944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG3	NM_001944.3	c.382C>G	p.Arg128Gly	missense_variant	Exon 5 of 16	ENST00000257189.5	NP_001935.2
DSG3	XM_011525850.3	c.382C>G	p.Arg128Gly	missense_variant	Exon 5 of 16		XP_011524152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG3	ENST00000257189.5	c.382C>G	p.Arg128Gly	missense_variant	Exon 5 of 16	1	NM_001944.3	ENSP00000257189.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250312 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135250

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461000 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.33
Sift	Benign	0.19	T
Sift4G	Benign	0.089	T
Polyphen		0.90	P
Vest4		0.39
MutPred		0.63		Loss of sheet (P = 0.0817);
MVP		0.73
MPC		0.52
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.40
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs771333335; hg19: chr18-29039005; COSMIC: COSV57126195;