rs869312850

Variant names:

• chr3-55474476-C-A
• rs869312850
• NM_003392.7:c.545G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-55474476-C-A
• chr3-55474476-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_003392.7(WNT5A):​c.545G>T​(p.Cys182Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,400 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. C182S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WNT5A NM_003392.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• 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: 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 chr3-55474477-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 29819.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT5A	NM_003392.7	c.545G>T	p.Cys182Phe	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.545G>T	p.Cys182Phe	missense_variant	Exon 4 of 5	1	NM_003392.7	ENSP00000264634.4
WNT5A	ENST00000474267.5	c.545G>T	p.Cys182Phe	missense_variant	Exon 5 of 6	5		ENSP00000417310.1
WNT5A	ENST00000497027.5	c.500G>T	p.Cys167Phe	missense_variant	Exon 4 of 5	2		ENSP00000420104.1
WNT5A	ENST00000482079.1	c.500G>T	p.Cys167Phe	missense_variant	Exon 3 of 3	2		ENSP00000418184.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449400 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 43060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.00 AC: 0 AN: 84524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107352

Other (OTH) AF: 0.00 AC: 0 AN: 59896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

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	0.99
DEOGEN2	Pathogenic	0.97	D;D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.2	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.93	P;P;.;.
Vest4		0.93
MutPred		0.94		Gain of MoRF binding (P = 0.2227);Gain of MoRF binding (P = 0.2227);.;.;
MVP		0.69
MPC		2.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.98
Mutation Taster		=3/97	disease causing

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: rs869312850; hg19: chr3-55508504;