chr11-6630239-G-A

Variant names:

• chr11-6630239-G-A
• rs199544459
• NM_003737.4:c.4555C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003737.4(DCHS1):​c.4555C>T​(p.Pro1519Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,549,598 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1519P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: DCHS1 NM_003737.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.50
• Publications: 3 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008468181).
• BP6: Variant 11-6630239-G-A is Benign according to our data. Variant chr11-6630239-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376906.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00146 (222/152060) while in subpopulation NFE AF = 0.00259 (176/67940). AF 95% confidence interval is 0.00228. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003737.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	NM_003737.4	MANE Select	c.4555C>T	p.Pro1519Ser	missense	Exon 10 of 21	NP_003728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.4555C>T	p.Pro1519Ser	missense	Exon 10 of 21	ENSP00000299441.3

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 151946 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00133 AC: 197 AN: 147812 AF XY: 0.00138

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00257 AC: 3585 AN: 1397538 Hom.: 11 Cov.: 31 AF XY: 0.00242 AC XY: 1672 AN XY: 690502

African (AFR) AF: 0.000284 AC: 9 AN: 31720

American (AMR) AF: 0.000244 AC: 9 AN: 36878

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 35890

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79988

European-Finnish (FIN) AF: 0.000530 AC: 22 AN: 41476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00322 AC: 3482 AN: 1082552

Other (OTH) AF: 0.00101 AC: 59 AN: 58136

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74354

African (AFR) AF: 0.000770 AC: 32 AN: 41556

American (AMR) AF: 0.000720 AC: 11 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00259 AC: 176 AN: 67940

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00151

ESP6500AA AF: 0.000565 AC: 2

ESP6500EA AF: 0.000996 AC: 7

ExAC AF: 0.000872 AC: 93

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.21	N
PhyloP100		3.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.15
Sift	Benign	0.47	T
Sift4G	Uncertain	0.039	D
Polyphen		0.27	B
Vest4		0.28
MVP		0.37
MPC		1.7
ClinPred		0.017	T
GERP RS		4.2
Varity_R		0.038
gMVP		0.54
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs199544459; hg19: chr11-6651470; COSMIC: COSV99079051; COSMIC: COSV99079051;