4-84801725-T-C

Position:

• chr4-84801725-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014991.6(WDFY3):​c.2747A>G​(p.Asp916Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDFY3 NM_014991.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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-AS1 (HGNC:40935): (WDFY3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19857132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDFY3	NM_014991.6	c.2747A>G	p.Asp916Gly	missense_variant	17/68	ENST00000295888.9
WDFY3-AS1	NR_046707.1	n.91-1535T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDFY3	ENST00000295888.9	c.2747A>G	p.Asp916Gly	missense_variant	17/68	1	NM_014991.6	P1
WDFY3-AS1	ENST00000510449.2	n.142-1535T>C		intron_variant, non_coding_transcript_variant		3
WDFY3	ENST00000514711.2	c.1283A>G	p.Asp428Gly	missense_variant	7/57	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460498 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.2747A>G (p.D916G) alteration is located in exon 17 (coding exon 14) of the WDFY3 gene. This alteration results from a A to G substitution at nucleotide position 2747, causing the aspartic acid (D) at amino acid position 916 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.032
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Polyphen		0.033	B
Vest4		0.56
MutPred		0.17		Gain of helix (P = 0.0325);
MVP		0.082
MPC		0.54
ClinPred		0.73	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-85722878;