rs1553924800

Variant names:

• chr4-84715350-G-A
• rs1553924800
• NM_014991.6:c.7909C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_014991.6(WDFY3):​c.7909C>T​(p.Arg2637Trp) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005399786: "In vitro functional expression studies showed that cells transfected with the WDFY3 p.(Arg637Trp) variant had increased levels of DVL3 compared to controls, suggesting abnormal activation of WNT signalling resulting in impaired cortical development and microcephaly. Additionally, drosophila transfected with the WDFY3 p.(Arg2637Trp) variant displayed a small brain volume, recapitulating disease phenotype." PMID:27008544" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2637Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WDFY3 NM_014991.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.98
• Publications: 1 publications found

Genes affected

WDFY3 (HGNC:20751): (WD repeat and FYVE domain containing 3) This gene encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of these aggregated proteins. However, it is not necessary for starvation-induced macroautophagy. [provided by RefSeq, May 2010]

WDFY3 Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005399786: "In vitro functional expression studies showed that cells transfected with the WDFY3 p.(Arg637Trp) variant had increased levels of DVL3 compared to controls, suggesting abnormal activation of WNT signalling resulting in impaired cortical development and microcephaly. Additionally, drosophila transfected with the WDFY3 p.(Arg2637Trp) variant displayed a small brain volume, recapitulating disease phenotype." PMID: 27008544; SCV003194829: Published functional studies demonstrate a damaging effect as luciferase assay suggest a dominant negative role in attenuating Wnt signaling, and cell imaging and western blot assay show impaired autophagy-dependent removal of DVL3 aggregates (PMID: 27008544)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 4-84715350-G-A is Pathogenic according to our data. Variant chr4-84715350-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 446237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014991.6. 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
	WDFY3	NM_014991.6	MANE Select	c.7909C>T	p.Arg2637Trp	missense	Exon 50 of 68	NP_055806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDFY3	ENST00000295888.9	TSL:1 MANE Select	c.7909C>T	p.Arg2637Trp	missense	Exon 50 of 68	ENSP00000295888.4	Q8IZQ1-1
	WDFY3	ENST00000514711.2	TSL:2	c.6349C>T	p.Arg2117Trp	missense	Exon 39 of 57	ENSP00000424987.2	H0Y9T6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Microcephaly 18, primary, autosomal dominant (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.57		Loss of solvent accessibility (P = 0.0299)
MVP		0.41
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.88
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553924800; hg19: chr4-85636503; COSMIC: COSV55715813;