Genetic Variant WDFY4:p.Ser1528Pro (chr10-48805357-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001394531.1(WDFY4):c.4582T>C(p.Ser1528Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,549,058 control chromosomes in the GnomAD database, including 111,682 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 18690 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92992 hom. )

Consequence

WDFY4
NM_001394531.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.409

Publications

21 publications found

Variant links:

Genes affected

WDFY4 (HGNC:29323): (WDFY family member 4) Predicted to be involved in autophagy. Predicted to act upstream of or within with a positive effect on CD8-positive, alpha-beta T cell activation. Predicted to act upstream of or within antigen processing and presentation and cellular response to virus. Predicted to be located in early endosome and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

WDFY4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

WDFY4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.345476E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDFY4	NM_001394531.1 link	c.4582T>C	p.Ser1528Pro	missense_variant	Exon 26 of 62	ENST00000325239.12	NP_001381460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDFY4	ENST00000325239.12 link	c.4582T>C	p.Ser1528Pro	missense_variant	Exon 26 of 62	5	NM_001394531.1	ENSP00000320563.5		Q6ZS81-1
WDFY4	ENST00000374161.7 link	n.221T>C		non_coding_transcript_exon_variant	Exon 3 of 13	2

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69503

AN:

151812

Hom.:

18643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.712

Gnomad AMI

AF:

0.445

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.457

GnomAD2 exomes

AF:

0.410

AC:

63463

AN:

154822

AF XY:

0.405

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.406

Gnomad ASJ exome

AF:

0.351

Gnomad EAS exome

AF:

0.855

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.390

GnomAD4 exome

AF:

0.345

AC:

482586

AN:

1397128

Hom.:

92992

Cov.:

AF XY:

0.347

AC XY:

238867

AN XY:

689182

show subpopulations

African (AFR)

AF:

0.731

AC:

23113

AN:

31598

American (AMR)

AF:

0.408

AC:

14556

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

8872

AN:

25178

East Asian (EAS)

AF:

0.869

AC:

31042

AN:

35736

South Asian (SAS)

AF:

0.431

AC:

34184

AN:

79222

European-Finnish (FIN)

AF:

0.319

AC:

14989

AN:

46994

Middle Eastern (MID)

AF:

0.427

AC:

2433

AN:

5704

European-Non Finnish (NFE)

AF:

0.306

AC:

330438

AN:

1078954

Other (OTH)

AF:

0.396

AC:

22959

AN:

58046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17063

34125

51188

68250

85313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11282

22564

33846

45128

56410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.458

AC:

69619

AN:

151930

Hom.:

18690

Cov.:

AF XY:

0.458

AC XY:

34029

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.712

AC:

29525

AN:

41446

American (AMR)

AF:

0.413

AC:

6316

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1251

AN:

3470

East Asian (EAS)

AF:

0.843

AC:

4328

AN:

5134

South Asian (SAS)

AF:

0.459

AC:

2208

AN:

4814

European-Finnish (FIN)

AF:

0.321

AC:

3381

AN:

10546

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21109

AN:

67932

Other (OTH)

AF:

0.457

AC:

964

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1681

3361

5042

6722

8403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.379

Hom.:

34150

Bravo

AF:

0.478

TwinsUK

AF:

0.313

AC:

1160

ALSPAC

AF:

0.299

AC:

1151

ESP6500AA

AF:

0.730

AC:

1011

ESP6500EA

AF:

0.313

AC:

996

ExAC

AF:

0.386

AC:

10450

Asia WGS

AF:

0.645

AC:

2239

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.9

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0034

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.18

MetaRNN

Benign

7.3e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.76

PhyloP100

-0.41

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.050

REVEL

Benign

0.045

Sift

Benign

0.31

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.023

ClinPred

0.000022

GERP RS

1.5

Varity_R

0.089

gMVP

0.29

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over