rs117368891

Positions:

chr11-6640369-G-T

Variant summary

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

The NM_003737.4(DCHS1):c.1245C>A(p.Ser415Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,613,468 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 68 hom. )

Consequence

DCHS1
NM_003737.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

DCHS1 (HGNC:13681): (dachsous cadherin-related 1) This gene is a member of the cadherin superfamily whose members encode calcium-dependent cell-cell adhesion molecules. The encoded protein has a signal peptide, 27 cadherin repeat domains and a unique cytoplasmic region. This particular cadherin family member is expressed in fibroblasts but not in melanocytes or keratinocytes. The cell-cell adhesion of fibroblasts is thought to be necessary for wound healing. [provided by RefSeq, Jul 2008]

DCHS1 links:

(HGNC:):

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=0.009622633).

BP6

Variant 11-6640369-G-T is Benign according to our data. Variant chr11-6640369-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6640369-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00629 (959/152346) while in subpopulation NFE AF= 0.0115 (781/68042). AF 95% confidence interval is 0.0108. There are 6 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCHS1	NM_003737.4 linkuse as main transcript	c.1245C>A	p.Ser415Arg	missense_variant	2/21	ENST00000299441.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCHS1	ENST00000299441.5 linkuse as main transcript	c.1245C>A	p.Ser415Arg	missense_variant	2/21	1	NM_003737.4	P1
	ENST00000656961.1 linkuse as main transcript	n.309+8940G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00630

AC:

959

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00582

AC:

1454

AN:

249688

Hom.:

AF XY:

0.00570

AC XY:

770

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00667

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000623

Gnomad FIN exome

AF:

0.00543

Gnomad NFE exome

AF:

0.00991

Gnomad OTH exome

AF:

0.00672

GnomAD4 exome

AF:

0.00822

AC:

12008

AN:

1461122

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

5877

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.00865

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.00645

Gnomad4 NFE exome

AF:

0.00977

Gnomad4 OTH exome

AF:

0.00651

GnomAD4 genome

AF:

0.00629

AC:

959

AN:

152346

Hom.:

Cov.:

AF XY:

0.00569

AC XY:

424

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00554

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00594

AC:

721

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DCHS1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DCHS1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.27

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.0

REVEL

Benign

0.13

Sift

Benign

0.22

Sift4G

Uncertain

0.034

Polyphen

1.0

Vest4

0.69

MutPred

0.44

Loss of disorder (P = 0.1101);

MVP

0.41

MPC

0.37

ClinPred

0.020

GERP RS

5.7

Varity_R

0.11

gMVP

0.26

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