18-31354718-A-T

Position:

chr18-31354718-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000257192.5(DSG1):c.2522A>T(p.Tyr841Phe) variant causes a missense change. The variant allele was found at a frequency of 0.135 in 1,613,964 control chromosomes in the GnomAD database, including 15,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y841Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 1403 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13808 hom. )

Consequence

DSG1
ENST00000257192.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.42

Variant links:

Genes affected

DSG1 (HGNC:3048): (desmoglein 1) This gene encodes a member of the desmoglein protein subfamily. Desmogleins, along with desmocollins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmoglein family members on chromosome 18. The encoded protein has been identified as a target of auto-antibodies in the autoimmune skin blistering disease pemphigus foliaceus. Disruption of this gene has also been associated with the skin diseases palmoplantar keratoderma and erythroderma. [provided by RefSeq, Feb 2015]

DSG1 links:

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

DSG1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016768277).

BP6

Variant 18-31354718-A-T is Benign according to our data. Variant chr18-31354718-A-T is described in ClinVar as [Benign]. Clinvar id is 402803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG1	NM_001942.4 linkuse as main transcript	c.2522A>T	p.Tyr841Phe	missense_variant	15/15	ENST00000257192.5	NP_001933.2
DSG1-AS1	NR_110788.1 linkuse as main transcript	n.157-265T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG1	ENST00000257192.5 linkuse as main transcript	c.2522A>T	p.Tyr841Phe	missense_variant	15/15	1	NM_001942.4	ENSP00000257192	P1	Q02413-1
DSG1-AS1	ENST00000581856.5 linkuse as main transcript	n.96-265T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20509

AN:

151960

Hom.:

1402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.0891

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.130

AC:

32766

AN:

251356

Hom.:

2296

AF XY:

0.134

AC XY:

18252

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.0753

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.0961

Gnomad SAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.146

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.135

AC:

197066

AN:

1461886

Hom.:

13808

Cov.:

AF XY:

0.135

AC XY:

98133

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.138

Gnomad4 AMR exome

AF:

0.0776

Gnomad4 ASJ exome

AF:

0.205

Gnomad4 EAS exome

AF:

0.0939

Gnomad4 SAS exome

AF:

0.142

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.135

AC:

20530

AN:

152078

Hom.:

1403

Cov.:

AF XY:

0.133

AC XY:

9908

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.0891

Gnomad4 SAS

AF:

0.137

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.143

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.144

Hom.:

1232

Bravo

AF:

0.132

TwinsUK

AF:

0.134

AC:

496

ALSPAC

AF:

0.140

AC:

541

ESP6500AA

AF:

0.139

AC:

611

ESP6500EA

AF:

0.136

AC:

1169

ExAC

AF:

0.132

AC:

16030

Asia WGS

AF:

0.0910

AC:

318

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.151

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Palmoplantar keratoderma i, striate, focal, or diffuse

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Severe dermatitis-multiple allergies-metabolic wasting syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

0.00086

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.2

D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;.

Vest4

0.50

MPC

0.41

ClinPred

0.023

GERP RS

5.8

Varity_R

0.40

gMVP

0.48

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over