rs199544459

Positions:

• chr11-6630239-G-A

Variant summary

Our verdict is Benign. Variant got -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).

• 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 -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 id is 376906.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. 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. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCHS1	NM_003737.4	c.4555C>T	p.Pro1519Ser	missense_variant	10/21	ENST00000299441.5	NP_003728.1

Ensembl

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

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	Eurofins Ntd Llc (ga)	Sep 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	This variant is associated with the following publications: (PMID: 29165578) -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

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
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;