chr3-55474542-G-C

Variant names:

• chr3-55474542-G-C
• rs1553677971
• NM_003392.7:c.479C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003392.7(WNT5A):​c.479C>G​(p.Ser160Cys) variant causes a missense change. 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)
• Consequence: WNT5A NM_003392.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.29
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• PP5: Variant 3-55474542-G-C is Pathogenic according to our data. Variant chr3-55474542-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488060.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT5A	NM_003392.7	c.479C>G	p.Ser160Cys	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.479C>G	p.Ser160Cys	missense_variant	Exon 4 of 5	1	NM_003392.7	ENSP00000264634.4
WNT5A	ENST00000474267.5	c.479C>G	p.Ser160Cys	missense_variant	Exon 5 of 6	5		ENSP00000417310.1
WNT5A	ENST00000497027.5	c.434C>G	p.Ser145Cys	missense_variant	Exon 4 of 5	2		ENSP00000420104.1
WNT5A	ENST00000482079.1	c.434C>G	p.Ser145Cys	missense_variant	Exon 3 of 3	2		ENSP00000418184.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Robinow syndrome 1 Pathogenic:1

Jun 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
PhyloP100		5.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.59
MutPred		0.56		Loss of disorder (P = 0.0121);Loss of disorder (P = 0.0121);.;.;
MVP		0.42
MPC		1.6
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.63
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs1553677971; hg19: chr3-55508570;