rs146411944

Positions:

• chr11-6627101-T-A
• chr11-6627101-T-C
• chr11-6627101-T-G

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.5938A>T​(p.Thr1980Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,600 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1980T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: DCHS1 NM_003737.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021868944).
• BP6: Variant 11-6627101-T-A is Benign according to our data. Variant chr11-6627101-T-A is described in ClinVar as [Benign]. Clinvar id is 376899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00227 (344/151782) while in subpopulation AMR AF= 0.0157 (239/15246). AF 95% confidence interval is 0.014. There are 7 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCHS1	NM_003737.4	c.5938A>T	p.Thr1980Ser	missense_variant	14/21	ENST00000299441.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCHS1	ENST00000299441.5	c.5938A>T	p.Thr1980Ser	missense_variant	14/21	1	NM_003737.4	P1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 151664 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00595 AC: 1488 AN: 250284 Hom.: 32 AF XY: 0.00465 AC XY: 630 AN XY: 135520

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000709

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00160 AC: 2331 AN: 1460818 Hom.: 41 Cov.: 71 AF XY: 0.00140 AC XY: 1019 AN XY: 726632

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0366

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00461

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.000354

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00227 AC: 344 AN: 151782 Hom.: 7 Cov.: 33 AF XY: 0.00213 AC XY: 158 AN XY: 74200

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.000672 Hom.: 1

Bravo AF: 0.00385

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00492 AC: 597

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.70
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.098
Sift	Benign	0.74	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.27		Gain of phosphorylation at T1980 (P = 0.0723);
MVP		0.46
MPC		0.17
ClinPred		0.0034	T
GERP RS		4.0
Varity_R		0.019
gMVP		0.18

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: rs146411944; hg19: chr11-6648332;