3-55474534-C-T

Variant names:

• chr3-55474534-C-T
• NM_003392.7:c.487G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: WNT5A NM_003392.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	c.487G>A	p.Gly163Ser	missense_variant	Exon 4 of 5	ENST00000264634.9	NP_003383.4

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1405602 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 694452

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: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome Cov.: 30

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	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
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	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.052	D
MutationAssessor	Benign	1.2	L;L;.;.
PrimateAI	Uncertain	0.71	T
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	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.83

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: chr3-55508562; COSMIC: COSV52838466; COSMIC: COSV52838466;