rs4758443

Positions:

• chr11-6627193-G-A
• chr11-6627193-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003737.4(DCHS1):​c.5846C>T​(p.Thr1949Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,612,666 control chromosomes in the GnomAD database, including 106,094 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8241 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97853 hom.)
• Consequence: DCHS1 NM_003737.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.768

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=0.00938046).
• BP6: Variant 11-6627193-G-A is Benign according to our data. Variant chr11-6627193-G-A is described in ClinVar as [Benign]. Clinvar id is 259140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6627193-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCHS1	NM_003737.4	c.5846C>T	p.Thr1949Met	missense_variant	14/21	ENST00000299441.5	NP_003728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCHS1	ENST00000299441.5	c.5846C>T	p.Thr1949Met	missense_variant	14/21	1	NM_003737.4	ENSP00000299441.3

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47583 AN: 151860 Hom.: 8244 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.356 AC: 88937 AN: 250142 Hom.: 16256 AF XY: 0.356 AC XY: 48264 AN XY: 135438

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.299

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.363 AC: 530870 AN: 1460688 Hom.: 97853 Cov.: 69 AF XY: 0.363 AC XY: 263555 AN XY: 726618

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.313 AC: 47585 AN: 151978 Hom.: 8241 Cov.: 32 AF XY: 0.314 AC XY: 23351 AN XY: 74264

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.350

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.332

Alfa AF: 0.358 Hom.: 18566

Bravo AF: 0.302

TwinsUK AF: 0.360 AC: 1334

ALSPAC AF: 0.368 AC: 1417

ESP6500AA AF: 0.172 AC: 758

ESP6500EA AF: 0.368 AC: 3160

ExAC AF: 0.354 AC: 42968

Asia WGS AF: 0.338 AC: 1178 AN: 3478

EpiCase AF: 0.365

EpiControl AF: 0.367

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Van Maldergem syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.84
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.067
Sift	Benign	0.20	T
Sift4G	Benign	0.075	T
Polyphen		0.023	B
Vest4		0.10
MPC		0.21
ClinPred		0.0033	T
GERP RS		2.3
Varity_R		0.024
gMVP		0.30

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: rs4758443; hg19: chr11-6648424; COSMIC: COSV55032146; COSMIC: COSV55032146;