rs1553924800

Positions:

• chr4-84715350-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

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 (★). 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, single submitter P:2
• 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 Likely_pathogenic. Variant got 6 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_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDFY3	ENST00000295888.9	c.7909C>T	p.Arg2637Trp	missense_variant	50/68	1	NM_014991.6	P1
WDFY3	ENST00000514711.2	c.6349C>T	p.Arg2117Trp	missense_variant	39/57	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2023

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 (Kadir et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27008544) -

Microcephaly 18, primary, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 19, 2024

- -

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;.
MutationTaster	Benign	1.0	D;D
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;