rs117368891

chr11-6640369-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.75

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]

(HGNC:):

ACMG classification

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 GnomAd at 6 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 959 AN: 152228 Hom.: 6 Cov.: 33

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.: 7 AF XY: 0.00570 AC XY: 770 AN XY: 135002

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.: 68 Cov.: 31 AF XY: 0.00809 AC XY: 5877 AN XY: 726798

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.: 6 Cov.: 33 AF XY: 0.00569 AC XY: 424 AN XY: 74488

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.: 14

Bravo AF: 0.00554

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00594 AC: 721

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 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	Invitae	Jan 31, 2024	- -

DCHS1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.27	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.44		Loss of disorder (P = 0.1101);
MVP		0.41
MPC		0.37
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs117368891; hg19: chr11-6661600;