Genetic Variant WNT5A:p.Gly163Ser (chr3-55474534-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_003392.7(WNT5A):c.487G>A(p.Gly163Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000285 in 1,405,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G163R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

WNT5A
NM_003392.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.97

Publications

0 publications found

Variant links:

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]

WNT5A Gene-Disease associations (from GenCC):

autosomal dominant Robinow syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autosomal dominant Robinow syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

WNT5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-55474534-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160316.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT5A	NM_003392.7 link	c.487G>A	p.Gly163Ser	missense_variant	Exon 4 of 5	ENST00000264634.9	NP_003383.4	P41221-1A0A384N611B3KQX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNT5A	ENST00000264634.9 link	c.487G>A	p.Gly163Ser	missense_variant	Exon 4 of 5	1	NM_003392.7	ENSP00000264634.4	P41221-1
WNT5A	ENST00000474267.5 link	c.487G>A	p.Gly163Ser	missense_variant	Exon 5 of 6	5		ENSP00000417310.1	P41221-1
WNT5A	ENST00000497027.5 link	c.442G>A	p.Gly148Ser	missense_variant	Exon 4 of 5	2		ENSP00000420104.1	P41221-2
WNT5A	ENST00000482079.1 link	c.442G>A	p.Gly148Ser	missense_variant	Exon 3 of 3	2		ENSP00000418184.1	C9J8I8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1405602

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31972

American (AMR)

AF:

0.00

AC:

AN:

35898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24818

East Asian (EAS)

AF:

0.00

AC:

AN:

36712

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085702

Other (OTH)

AF:

0.0000344

AC:

AN:

58204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;.;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.052

MutationAssessor

Benign

1.2

L;L;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.46

T;T;T;D

Sift4G

Benign

0.23

T;T;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.66

MutPred

0.87

Loss of catalytic residue at G163 (P = 0.0508);Loss of catalytic residue at G163 (P = 0.0508);.;.;

MVP

0.23

MPC

1.3

ClinPred

0.99

GERP RS

4.6

Varity_R

0.51

gMVP

0.83

Mutation Taster

=29/71

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over