rs3752095

Variant names:

• chr18-31354718-A-T
• rs3752095
• NM_001942.4:c.2522A>T

Variant summary

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

The NM_001942.4(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 NM_001942.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.42
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
DSG1	NM_001942.4	c.2522A>T	p.Tyr841Phe	missense_variant	Exon 15 of 15	ENST00000257192.5	NP_001933.2
DSG1-AS1	NR_110788.1	n.157-265T>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG1	ENST00000257192.5	c.2522A>T	p.Tyr841Phe	missense_variant	Exon 15 of 15	1	NM_001942.4	ENSP00000257192.4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20509 AN: 151960 Hom.: 1402 Cov.: 32

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

GnomAD2 exomes AF: 0.130 AC: 32766 AN: 251356 AF XY: 0.134

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 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.: 32 AF XY: 0.135 AC XY: 98133 AN XY: 727246

African (AFR) AF: 0.138 AC: 4622 AN: 33480

American (AMR) AF: 0.0776 AC: 3472 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5366 AN: 26136

East Asian (EAS) AF: 0.0939 AC: 3727 AN: 39700

South Asian (SAS) AF: 0.142 AC: 12226 AN: 86258

European-Finnish (FIN) AF: 0.118 AC: 6314 AN: 53420

Middle Eastern (MID) AF: 0.220 AC: 1268 AN: 5768

European-Non Finnish (NFE) AF: 0.137 AC: 151866 AN: 1112004

Other (OTH) AF: 0.136 AC: 8205 AN: 60396

GnomAD4 genome AF: 0.135 AC: 20530 AN: 152078 Hom.: 1403 Cov.: 32 AF XY: 0.133 AC XY: 9908 AN XY: 74332

African (AFR) AF: 0.134 AC: 5553 AN: 41466

American (AMR) AF: 0.109 AC: 1669 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 740 AN: 3468

East Asian (EAS) AF: 0.0891 AC: 460 AN: 5164

South Asian (SAS) AF: 0.137 AC: 660 AN: 4810

European-Finnish (FIN) AF: 0.111 AC: 1173 AN: 10592

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9719 AN: 67964

Other (OTH) AF: 0.141 AC: 298 AN: 2112

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

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Palmoplantar keratoderma i, striate, focal, or diffuse Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		6.4
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.48
Mutation Taster		=90/10	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: rs3752095; hg19: chr18-28934681; COSMIC: COSV57139864; COSMIC: COSV57139864;