4-84677238-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_014991.6(WDFY3):c.10418G>A(p.Arg3473Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
WDFY3
NM_014991.6 missense
NM_014991.6 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 7.50
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
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, 0.828
BS2
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WDFY3 | NM_014991.6 | c.10418G>A | p.Arg3473Gln | missense_variant | 67/68 | ENST00000295888.9 | NP_055806.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WDFY3 | ENST00000295888.9 | c.10418G>A | p.Arg3473Gln | missense_variant | 67/68 | 1 | NM_014991.6 | ENSP00000295888.4 | ||
WDFY3 | ENST00000425179.2 | n.1170G>A | non_coding_transcript_exon_variant | 4/5 | 1 | |||||
WDFY3 | ENST00000514711.2 | c.8858G>A | p.Arg2953Gln | missense_variant | 56/57 | 2 | ENSP00000424987.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251452Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727244
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Nov 30, 2022 | ACMG categories: PM2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0536);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at