rs387906663

Positions:

• chr3-55474477-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_003392.7(WNT5A):​c.544T>C​(p.Cys182Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WNT5A NM_003392.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.06

Genes affected

WNT5A (HGNC:12784): (Wnt family member 5A) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis. Mutations in this gene are the cause of autosomal dominant Robinow syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-55474477-A-G is Pathogenic according to our data. Variant chr3-55474477-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29819.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT5A	NM_003392.7	c.544T>C	p.Cys182Arg	missense_variant	4/5	ENST00000264634.9	NP_003383.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT5A	ENST00000264634.9	c.544T>C	p.Cys182Arg	missense_variant	4/5	1	NM_003392.7	ENSP00000264634.4
WNT5A	ENST00000474267.5	c.544T>C	p.Cys182Arg	missense_variant	5/6	5		ENSP00000417310.1
WNT5A	ENST00000497027.5	c.499T>C	p.Cys167Arg	missense_variant	4/5	2		ENSP00000420104.1
WNT5A	ENST00000482079.1	c.499T>C	p.Cys167Arg	missense_variant	3/3	2		ENSP00000418184.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449372 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Robinow syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed missense c.544T>Cp.Cys182Arg variant in WNT5A gene has been reported in individuals affected with Robinow syndrome-1 Li P, et al., 2015; Roifman M, et al., 2015; Person AD, et al., 2010. Functional expression assays in zebrafish embryos showed that the mutant protein represented a hypomorphic allele partial loss of function Person AD, et al., 2010. The p.Cys182Arg variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on WNT5A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 182 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-10	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.97
MutPred		0.91		Gain of MoRF binding (P = 0.0054);Gain of MoRF binding (P = 0.0054);.;.;
MVP		0.70
MPC		2.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.99

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: rs387906663; hg19: chr3-55508505;