rs199544459

chr11-6630239-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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

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]

ACMG classification

Verdict is Benign. Variant got -9 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 id is 376906.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr11-6630239-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCHS1	NM_003737.4	c.4555C>T	p.Pro1519Ser	missense_variant	10/21	ENST00000299441.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCHS1	ENST00000299441.5	c.4555C>T	p.Pro1519Ser	missense_variant	10/21	1	NM_003737.4	P1

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

GnomAD3 exomes AF: 0.00133 AC: 197 AN: 147812 Hom.: 1 AF XY: 0.00138 AC XY: 112 AN XY: 81250

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 SAS 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

Gnomad4 AFR exome AF: 0.000284

Gnomad4 AMR exome AF: 0.000244

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.000530

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00101

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

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00274 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	This variant is associated with the following publications: (PMID: 29165578) -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.95	D
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

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