18-31457023-A-T

Variant names:

• chr18-31457023-A-T
• rs747978629
• NM_001944.3:c.115A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001944.3(DSG3):​c.115A>T​(p.Thr39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DSG3 NM_001944.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0738087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG3	NM_001944.3	c.115A>T	p.Thr39Ser	missense_variant	Exon 3 of 16	ENST00000257189.5	NP_001935.2
DSG3	XM_011525850.3	c.115A>T	p.Thr39Ser	missense_variant	Exon 3 of 16		XP_011524152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG3	ENST00000257189.5	c.115A>T	p.Thr39Ser	missense_variant	Exon 3 of 16	1	NM_001944.3	ENSP00000257189.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249556 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460700 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115A>T (p.T39S) alteration is located in exon 3 (coding exon 3) of the DSG3 gene. This alteration results from a A to T substitution at nucleotide position 115, causing the threonine (T) at amino acid position 39 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.70
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.091
Sift	Benign	0.34	T
Sift4G	Benign	0.12	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.19		Loss of methylation at K44 (P = 0.1071);
MVP		0.63
MPC		0.098
ClinPred		0.045	T
GERP RS		4.0
Varity_R		0.035
gMVP		0.31

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: rs747978629; hg19: chr18-29036986;