Genetic Variant WAPL:p.Val124Ile (chr10-86517700-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_015045.5(WAPL):c.370G>A(p.Val124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,938 control chromosomes in the GnomAD database, including 58,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.21 ( 4021 hom., cov: 33)

Exomes 𝑓: 0.27 ( 54318 hom. )

Consequence

WAPL
NM_015045.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

24 publications found

Variant links:

Genes affected

WAPL (HGNC:23293): (WAPL cohesin release factor) Involved in several processes, including negative regulation of DNA replication; negative regulation of chromatin binding activity; and regulation of sister chromatid cohesion. Located in several cellular components, including Golgi apparatus; intercellular bridge; and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

WAPL Gene-Disease associations (from GenCC):

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

WAPL 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=0.0038123429).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAPL	NM_015045.5 link	c.370G>A	p.Val124Ile	missense_variant	Exon 2 of 19	ENST00000298767.10	NP_055860.1	Q7Z5K2-1A8K273B2RTX8
WAPL	NM_001318328.2 link	c.370G>A	p.Val124Ile	missense_variant	Exon 2 of 19		NP_001305257.1	Q7Z5K2A8K273B2RTX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAPL	ENST00000298767.10 link	c.370G>A	p.Val124Ile	missense_variant	Exon 2 of 19	1	NM_015045.5	ENSP00000298767.4		Q7Z5K2-1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32204

AN:

152014

Hom.:

4022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0940

Gnomad AMI

AF:

0.373

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.304

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.174

GnomAD2 exomes

AF:

0.241

AC:

60653

AN:

251340

AF XY:

0.253

show subpopulations

Gnomad AFR exome

AF:

0.0946

Gnomad AMR exome

AF:

0.0996

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.290

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.267

AC:

389965

AN:

1461806

Hom.:

54318

Cov.:

AF XY:

0.270

AC XY:

196679

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0898

AC:

3007

AN:

33476

American (AMR)

AF:

0.105

AC:

4675

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

6568

AN:

26132

East Asian (EAS)

AF:

0.169

AC:

6710

AN:

39686

South Asian (SAS)

AF:

0.350

AC:

30227

AN:

86254

European-Finnish (FIN)

AF:

0.293

AC:

15621

AN:

53404

Middle Eastern (MID)

AF:

0.201

AC:

1157

AN:

5766

European-Non Finnish (NFE)

AF:

0.276

AC:

307066

AN:

1111970

Other (OTH)

AF:

0.247

AC:

14934

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

17267

34534

51801

69068

86335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.212

AC:

32203

AN:

152132

Hom.:

4021

Cov.:

AF XY:

0.214

AC XY:

15884

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0938

AC:

3898

AN:

41536

American (AMR)

AF:

0.126

AC:

1932

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3472

East Asian (EAS)

AF:

0.198

AC:

1028

AN:

5186

South Asian (SAS)

AF:

0.339

AC:

1635

AN:

4820

European-Finnish (FIN)

AF:

0.304

AC:

3199

AN:

10538

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18907

AN:

67978

Other (OTH)

AF:

0.172

AC:

364

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1277

2554

3832

5109

6386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.249

Hom.:

17394

Bravo

AF:

0.189

TwinsUK

AF:

0.272

AC:

1007

ALSPAC

AF:

0.278

AC:

1073

ESP6500AA

AF:

0.105

AC:

462

ESP6500EA

AF:

0.282

AC:

2426

ExAC

AF:

0.247

AC:

30049

EpiCase

AF:

0.262

EpiControl

AF:

0.255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.075

T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.46

.;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.11

N;.

REVEL

Benign

0.080

Sift

Benign

0.089

T;.

Sift4G

Benign

0.40

T;T

Polyphen

0.014

B;B

Vest4

0.012

MPC

0.14

ClinPred

0.0013

GERP RS

1.1

Varity_R

0.033

gMVP

0.11

Mutation Taster

=99/1

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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10-86517700-C-T

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