chr11-6621810-T-A

Position:

• chr11-6621810-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003737.4(DCHS1):​c.9866A>T​(p.Glu3289Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DCHS1 NM_003737.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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-AS1 (HGNC:40650): (DCHS1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCHS1	NM_003737.4	c.9866A>T	p.Glu3289Val	missense_variant	21/21	ENST00000299441.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCHS1	ENST00000299441.5	c.9866A>T	p.Glu3289Val	missense_variant	21/21	1	NM_003737.4	P1
DCHS1-AS1	ENST00000526456.1	n.360T>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448962 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000697

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 3289 of the DCHS1 protein (p.Glu3289Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DCHS1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCHS1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.16		Loss of solvent accessibility (P = 0.0509);
MVP		0.43
MPC		0.55
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6643041;