dbSNP rs756862725: DSG4:p.Glu28Lys (chr18-31385169-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_177986.5(DSG4):c.82G>A(p.Glu28Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DSG4
NM_177986.5 missense, splice_region

Scores

Splicing: ADA: 0.1128

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.28

Variant links:

Genes affected

DSG4 (HGNC:21307): (desmoglein 4) This gene encodes a member of the desmoglein subgroup of desmosomal cadherins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein is a transmembrane component of desmosomes and may play a role in cell-cell adhesion in epithelial cells. Mutations in the gene are associated with localized autosomal recessive hypotrichosis and monilethrix, characterized by impaired hair growth. [provided by RefSeq, May 2016]

DSG4 links:

DSG1-AS1 (HGNC:51115): (DSG1 antisense RNA 1)

DSG1-AS1 links:

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ACMG classification

Classification made for transcript

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=0.21886638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG4	NM_177986.5 link	c.82G>A	p.Glu28Lys	missense_variant, splice_region_variant	Exon 2 of 16	ENST00000308128.9	NP_817123.1	Q86SJ6-1
DSG4	NM_001134453.3 link	c.82G>A	p.Glu28Lys	missense_variant, splice_region_variant	Exon 2 of 15		NP_001127925.1	Q86SJ6-2
DSG1-AS1	NR_110788.1 link	n.157-30716C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG4	ENST00000308128.9 link	c.82G>A	p.Glu28Lys	missense_variant, splice_region_variant	Exon 2 of 16	1	NM_177986.5	ENSP00000311859.4		Q86SJ6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246904

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133478

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430324

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.041

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0092

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.13

Sift

Benign

0.16

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0040

B;B

Vest4

0.69

MutPred

0.48

Gain of ubiquitination at E28 (P = 0.0311);Gain of ubiquitination at E28 (P = 0.0311);

MVP

0.61

MPC

0.037

ClinPred

0.45

GERP RS

4.8

Varity_R

0.20

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over