11-6641235-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003737.4(DCHS1):c.379G>A(p.Val127Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00783 in 1,613,764 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 58 hom. )

Consequence

DCHS1
NM_003737.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.09

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

mitral valve prolapse, myxomatous 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
van Maldergem syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
familial mitral valve prolapse
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
van Maldergem syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DCHS1 links:

ENSG00000255410 (HGNC:):

ENSG00000255410 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008645952).

BP6

Variant 11-6641235-C-T is Benign according to our data. Variant chr11-6641235-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376786.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00529 (806/152354) while in subpopulation SAS AF = 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 2 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCHS1	NM_003737.4 link	c.379G>A	p.Val127Ile	missense_variant	Exon 2 of 21	ENST00000299441.5	NP_003728.1	Q96JQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCHS1	ENST00000299441.5 link	c.379G>A	p.Val127Ile	missense_variant	Exon 2 of 21	1	NM_003737.4	ENSP00000299441.3		Q96JQ0
ENSG00000255410	ENST00000656961.1 link	n.309+9806C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

807

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0105

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00827

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00623

AC:

1560

AN:

250544

AF XY:

0.00672

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00814

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00809

AC:

11824

AN:

1461410

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

5893

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.00315

AC:

141

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00566

AC:

148

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0122

AC:

1051

AN:

86258

European-Finnish (FIN)

AF:

0.00192

AC:

102

AN:

53110

Middle Eastern (MID)

AF:

0.00745

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00880

AC:

9781

AN:

1111864

Other (OTH)

AF:

0.00828

AC:

500

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

836

1673

2509

3346

4182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00529

AC:

806

AN:

152354

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

379

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41592

American (AMR)

AF:

0.00471

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0108

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00828

AC:

563

AN:

68032

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00757

Hom.:

Bravo

AF:

0.00570

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00722

AC:

ExAC

AF:

0.00619

AC:

751

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00796

EpiControl

AF:

0.00782

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign