rs1553924800

Positions:

• chr4-84715350-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 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 (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WDFY3. . Gene score misZ 5.8174 (greater than the threshold 3.09). Trascript score misZ 7.6797 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, complex neurodevelopmental disorder, autism spectrum disorder.
• 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 id is 446237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDFY3	NM_014991.6	c.7909C>T	p.Arg2637Trp	missense_variant	50/68	ENST00000295888.9	NP_055806.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDFY3	ENST00000295888.9	c.7909C>T	p.Arg2637Trp	missense_variant	50/68	1	NM_014991.6	ENSP00000295888.4
WDFY3	ENST00000514711.2	c.6349C>T	p.Arg2117Trp	missense_variant	39/57	2		ENSP00000424987.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 18, primary, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder (MONDO:0700092), WDFY3-related. A macrocephaly phenotype is known to be caused by loss of function variants, while microcephaly 18, primary (MIM#617520) is likely due to gain of function and increased WNT signalling (PMID: 31327001, 27008544). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg2637Gln) has been classified as a VUS by a clinical laboratory in ClinVar. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by a clinical laboratory in ClinVar and has also been reported in a family with primary microcephaly and mild to moderate intellectual disability (PMID: 27008544). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been reported to segregate in a family with primary microcephaly and mild-moderate intellectual disability. Linkage analysis performed on this family showed a ~9 Mb haplotype shared among the affected individuals, however this study only reported genotyping in one of the affected individuals (PMID: 27008544). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. 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). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2024

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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27008544) -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553924800; hg19: chr4-85636503; COSMIC: COSV55715813;