chr4-84675083-G-A

Variant names:

• chr4-84675083-G-A
• rs76117213
• NM_014991.6:c.10458-2092C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014991.6(WDFY3):​c.10458-2092C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 151,610 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.019 (34 hom., cov: 31)
• Consequence: WDFY3 NM_014991.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0189 (2861/151610) while in subpopulation NFE AF = 0.0268 (1820/67900). AF 95% confidence interval is 0.0258. There are 34 homozygotes in GnomAd4. There are 1399 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2861 AD gene.

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.10458-2092C>T		intron	N/A	NP_055806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDFY3	ENST00000295888.9	TSL:1 MANE Select	c.10458-2092C>T		intron	N/A	ENSP00000295888.4	Q8IZQ1-1
	WDFY3	ENST00000425179.2	TSL:1	n.1210-2092C>T		intron	N/A
	WDFY3	ENST00000514711.2	TSL:2	c.8898-2092C>T		intron	N/A	ENSP00000424987.2	H0Y9T6

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2861 AN: 151492 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.00894

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00463

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00251

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0189 AC: 2861 AN: 151610 Hom.: 34 Cov.: 31 AF XY: 0.0189 AC XY: 1399 AN XY: 74010

African (AFR) AF: 0.00892 AC: 369 AN: 41378

American (AMR) AF: 0.0164 AC: 250 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 16 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00251 AC: 12 AN: 4772

European-Finnish (FIN) AF: 0.0313 AC: 328 AN: 10480

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1820 AN: 67900

Other (OTH) AF: 0.0176 AC: 37 AN: 2100

Alfa AF: 0.0155 Hom.: 5

Bravo AF: 0.0167

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.3
DANN	Benign	0.35
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs76117213;

hg19: chr4-85596236;