Genetic Variant NM_001394531.1:c.9353C>T (chr10-48978370-C-T) – 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.9353C>T(p.Pro3118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,550,288 control chromosomes in the GnomAD database, including 188,020 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 0.45 ( 15608 hom., cov: 32)

Exomes 𝑓: 0.49 ( 172412 hom. )

Consequence

WDFY4
NM_001394531.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.131

Publications

22 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:

ENSG00000233665 (HGNC:):

ENSG00000233665 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=2.1889806E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDFY4	NM_001394531.1 link	c.9353C>T	p.Pro3118Leu	missense_variant	Exon 60 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.9353C>T	p.Pro3118Leu	missense_variant	Exon 60 of 62	5	NM_001394531.1	ENSP00000320563.5		Q6ZS81-1

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

68110

AN:

151862

Hom.:

15609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.431

Gnomad ASJ

AF:

0.421

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.477

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.511

Gnomad OTH

AF:

0.432

GnomAD2 exomes

AF:

0.451

AC:

69080

AN:

153094

AF XY:

0.456

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.425

Gnomad EAS exome

AF:

0.322

Gnomad FIN exome

AF:

0.420

Gnomad NFE exome

AF:

0.512

Gnomad OTH exome

AF:

0.458

GnomAD4 exome

AF:

0.493

AC:

689475

AN:

1398308

Hom.:

172412

Cov.:

AF XY:

0.492

AC XY:

339386

AN XY:

689684

show subpopulations

African (AFR)

AF:

0.360

AC:

11366

AN:

31570

American (AMR)

AF:

0.405

AC:

14409

AN:

35584

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

10750

AN:

25124

East Asian (EAS)

AF:

0.253

AC:

9020

AN:

35678

South Asian (SAS)

AF:

0.473

AC:

37425

AN:

79112

European-Finnish (FIN)

AF:

0.427

AC:

20958

AN:

49118

Middle Eastern (MID)

AF:

0.411

AC:

2339

AN:

5694

European-Non Finnish (NFE)

AF:

0.515

AC:

555652

AN:

1078476

Other (OTH)

AF:

0.475

AC:

27556

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17934

35868

53801

71735

89669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16138

32276

48414

64552

80690

<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:

0.448

AC:

68132

AN:

151980

Hom.:

15608

Cov.:

AF XY:

0.445

AC XY:

33017

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.377

AC:

15606

AN:

41432

American (AMR)

AF:

0.430

AC:

6583

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

1463

AN:

3472

East Asian (EAS)

AF:

0.321

AC:

1653

AN:

5150

South Asian (SAS)

AF:

0.477

AC:

2297

AN:

4818

European-Finnish (FIN)

AF:

0.410

AC:

4333

AN:

10574

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.511

AC:

34703

AN:

67924

Other (OTH)

AF:

0.436

AC:

920

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1904

3808

5713

7617

9521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.479

Hom.:

31811

Bravo

AF:

0.444

TwinsUK

AF:

0.527

AC:

1954

ALSPAC

AF:

0.506

AC:

1949

ESP6500AA

AF:

0.376

AC:

521

ESP6500EA

AF:

0.494

AC:

1572

ExAC

AF:

0.392

AC:

10358

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.0

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0052

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.00022

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

N;.

PhyloP100

-0.13

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.088

Sift

Benign

0.35

T;.

Sift4G

Benign

0.13

T;.

Polyphen

0.0

B;.

Vest4

0.028

ClinPred

0.0049

GERP RS

-1.0

PromoterAI

-0.0012

Neutral

(source)

Varity_R

0.023

gMVP

0.19

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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