18-31376941-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_177986.5(DSG4):c.30C>T(p.Cys10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,612,720 control chromosomes in the GnomAD database, including 16,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1471 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15091 hom.)
• Consequence: DSG4 NM_177986.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.126

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]

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 18-31376941-C-T is Benign according to our data. Variant chr18-31376941-C-T is described in ClinVar as [Benign]. Clinvar id is 326416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31376941-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.126 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG4	NM_177986.5	c.30C>T	p.Cys10=	synonymous_variant	1/16	ENST00000308128.9
DSG1-AS1	NR_110788.1	n.157-22488G>A		intron_variant, non_coding_transcript_variant
DSG4	NM_001134453.3	c.30C>T	p.Cys10=	synonymous_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG4	ENST00000308128.9	c.30C>T	p.Cys10=	synonymous_variant	1/16	1	NM_177986.5	P2
DSG1-AS1	ENST00000581856.5	n.96-22488G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21154 AN: 151968 Hom.: 1472 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.138 AC: 34485 AN: 250536 Hom.: 2536 AF XY: 0.143 AC XY: 19321 AN XY: 135396

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0696

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.142 AC: 207172 AN: 1460630 Hom.: 15091 Cov.: 31 AF XY: 0.142 AC XY: 103389 AN XY: 726638

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.139 AC: 21166 AN: 152090 Hom.: 1471 Cov.: 32 AF XY: 0.138 AC XY: 10260 AN XY: 74352

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.137

Alfa AF: 0.148 Hom.: 2677

Bravo AF: 0.134

Asia WGS AF: 0.105 AC: 365 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.153

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Hypotrichosis 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	4.1
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: rs36101975; hg19: chr18-28956904; COSMIC: COSV57389432;