18-31333636-C-T

Position:

• chr18-31333636-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001942.4(DSG1):​c.732C>T​(p.Gly244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,032 control chromosomes in the GnomAD database, including 182,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14285 hom., cov: 32)
  • Exomes 𝑓: 0.47 (168163 hom.)
• Consequence: DSG1 NM_001942.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.39

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 18-31333636-C-T is Benign according to our data. Variant chr18-31333636-C-T is described in ClinVar as [Benign]. Clinvar id is 402802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31333636-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG1	NM_001942.4	c.732C>T	p.Gly244=	synonymous_variant	7/15	ENST00000257192.5	NP_001933.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG1	ENST00000257192.5	c.732C>T	p.Gly244=	synonymous_variant	7/15	1	NM_001942.4	ENSP00000257192	P1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62953 AN: 151716 Hom.: 14290 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.432

GnomAD3 exomes AF: 0.422 AC: 105978 AN: 251018 Hom.: 25574 AF XY: 0.438 AC XY: 59456 AN XY: 135630

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.0531

Gnomad SAS exome AF: 0.497

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.462

GnomAD4 exome AF: 0.470 AC: 687150 AN: 1461198 Hom.: 168163 Cov.: 44 AF XY: 0.473 AC XY: 343592 AN XY: 726950

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.0573

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.494

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.415 AC: 62965 AN: 151834 Hom.: 14285 Cov.: 32 AF XY: 0.417 AC XY: 30979 AN XY: 74204

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.0576

Gnomad4 SAS AF: 0.483

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.431

Alfa AF: 0.464 Hom.: 29797

Bravo AF: 0.384

Asia WGS AF: 0.288 AC: 1003 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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 -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.18
DANN	Benign	0.57

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

Other links and lift over

dbSNP: rs12967407; hg19: chr18-28913599; COSMIC: COSV57135633;