NM_003392.7:c.487_492dupGGCTGC

Variant names:

• chr3-55474528-T-TGCAGCC
• rs1553677967
• NM_003392.7:c.487_492dupGGCTGC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_003392.7(WNT5A):​c.487_492dupGGCTGC​(p.Cys164_Ser165insGlyCys) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: WNT5A NM_003392.7 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.83
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_003392.7
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003392.7.
• PP5: Variant 3-55474528-T-TGCAGCC is Pathogenic according to our data. Variant chr3-55474528-T-TGCAGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488054.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003392.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT5A	NM_003392.7	MANE Select	c.487_492dupGGCTGC	p.Cys164_Ser165insGlyCys	conservative_inframe_insertion	Exon 4 of 5	NP_003383.4
	WNT5A	NM_001256105.1		c.442_447dupGGCTGC	p.Cys149_Ser150insGlyCys	conservative_inframe_insertion	Exon 4 of 5	NP_001243034.1
	WNT5A	NM_001377271.1		c.442_447dupGGCTGC	p.Cys149_Ser150insGlyCys	conservative_inframe_insertion	Exon 4 of 5	NP_001364200.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT5A	ENST00000264634.9	TSL:1 MANE Select	c.487_492dupGGCTGC	p.Cys164_Ser165insGlyCys	conservative_inframe_insertion	Exon 4 of 5	ENSP00000264634.4
	WNT5A	ENST00000474267.5	TSL:5	c.487_492dupGGCTGC	p.Cys164_Ser165insGlyCys	conservative_inframe_insertion	Exon 5 of 6	ENSP00000417310.1
	WNT5A	ENST00000497027.5	TSL:2	c.442_447dupGGCTGC	p.Cys149_Ser150insGlyCys	conservative_inframe_insertion	Exon 4 of 5	ENSP00000420104.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant Robinow syndrome 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553677967; hg19: chr3-55508556;