18-31403566-C-T

Position:

chr18-31403566-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_177986.5(DSG4):c.1568C>T(p.Pro523Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0071 in 1,613,966 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 91 hom. )

Consequence

DSG4
NM_177986.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.12

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:):

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=0.0106598735).

BP6

Variant 18-31403566-C-T is Benign according to our data. Variant chr18-31403566-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00542 (825/152200) while in subpopulation SAS AF= 0.0197 (95/4818). AF 95% confidence interval is 0.0165. There are 5 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG4	NM_177986.5 linkuse as main transcript	c.1568C>T	p.Pro523Leu	missense_variant	11/16	ENST00000308128.9	NP_817123.1	Q86SJ6-1
DSG4	NM_001134453.3 linkuse as main transcript	c.1568C>T	p.Pro523Leu	missense_variant	11/15		NP_001127925.1	Q86SJ6-2
DSG1-AS1	NR_110788.1 linkuse as main transcript	n.156+23267G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSG4	ENST00000308128.9 linkuse as main transcript	c.1568C>T	p.Pro523Leu	missense_variant	11/16	1	NM_177986.5	ENSP00000311859.4	Q86SJ6-1
DSG4	ENST00000359747.4 linkuse as main transcript	c.1568C>T	p.Pro523Leu	missense_variant	11/15	1		ENSP00000352785.4	Q86SJ6-2
DSG1-AS1	ENST00000578477.5 linkuse as main transcript	n.156+23267G>A		intron_variant		3
DSG1-AS1	ENST00000581856.5 linkuse as main transcript	n.95+23267G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00542

AC:

825

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00766

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00794

AC:

1996

AN:

251402

Hom.:

AF XY:

0.00876

AC XY:

1190

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00893

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00873

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.00727

AC:

10633

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

5730

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00525

Gnomad4 ASJ exome

AF:

0.00995

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0193

Gnomad4 FIN exome

AF:

0.00200

Gnomad4 NFE exome

AF:

0.00696

Gnomad4 OTH exome

AF:

0.00830

GnomAD4 genome

AF:

0.00542

AC:

825

AN:

152200

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

397

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00556

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00766

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00686

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00861

AC:

1046

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00976

EpiControl

AF:

0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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	Dec 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypotrichosis 6

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

-0.061

MutationAssessor

Pathogenic

3.7

H;H

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.67

MVP

0.93

MPC

0.25

ClinPred

0.089

GERP RS

6.0

Varity_R

0.43

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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