rs4758443

Variant names:

• chr11-6627193-G-A
• rs4758443
• NM_003737.4:c.5846C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1949K) has been classified as Uncertain significance.

• 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
• Publications: 44 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)
• van Maldergem syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• familial mitral valve prolapse

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

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.5846C>T	p.Thr1949Met	missense	Exon 14 of 21	NP_003728.1	Q96JQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCHS1	ENST00000299441.5	TSL:1 MANE Select	c.5846C>T	p.Thr1949Met	missense	Exon 14 of 21	ENSP00000299441.3	Q96JQ0

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

GnomAD2 exomes AF: 0.356 AC: 88937 AN: 250142 AF XY: 0.356

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 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

African (AFR) AF: 0.150 AC: 5010 AN: 33476

American (AMR) AF: 0.343 AC: 15330 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10385 AN: 26136

East Asian (EAS) AF: 0.458 AC: 18186 AN: 39688

South Asian (SAS) AF: 0.300 AC: 25884 AN: 86258

European-Finnish (FIN) AF: 0.391 AC: 20583 AN: 52646

Middle Eastern (MID) AF: 0.373 AC: 2149 AN: 5766

European-Non Finnish (NFE) AF: 0.371 AC: 412002 AN: 1111654

Other (OTH) AF: 0.354 AC: 21341 AN: 60346

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

African (AFR) AF: 0.159 AC: 6580 AN: 41468

American (AMR) AF: 0.350 AC: 5344 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3468

East Asian (EAS) AF: 0.445 AC: 2293 AN: 5150

South Asian (SAS) AF: 0.314 AC: 1514 AN: 4814

European-Finnish (FIN) AF: 0.388 AC: 4094 AN: 10552

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25269 AN: 67928

Other (OTH) AF: 0.332 AC: 702 AN: 2114

Alfa AF: 0.348 Hom.: 25355

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Van Maldergem syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.77
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
Mutation Taster		=93/7	polymorphism (auto)

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