Genetic Variant NM_024911.7:c.1393G>A (chr1-68137903-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBA1

The NM_024911.7(WLS):c.1393G>A(p.Val465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,613,486 control chromosomes in the GnomAD database, including 114,104 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 0.31 ( 8137 hom., cov: 32)

Exomes 𝑓: 0.37 ( 105967 hom. )

Consequence

WLS
NM_024911.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.861

Publications

35 publications found

Variant links:

Genes affected

WLS (HGNC:30238): (Wnt ligand secretion mediator) Enables Wnt-protein binding activity and identical protein binding activity. Involved in positive regulation of cell communication and protein transport. Located in several cellular components, including Golgi apparatus; early endosome; and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

WLS links:

GNG12-AS1 (HGNC:43938): (GNG12, DIRAS3 and WLS antisense RNA 1)

GNG12-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.6033 (below the threshold of 3.09). Trascript score misZ: 1.7209 (below the threshold of 3.09). GenCC associations: The gene is linked to Zaki syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034739375).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WLS	NM_024911.7 link	c.1393G>A	p.Val465Ile	missense_variant	Exon 11 of 12	ENST00000262348.9	NP_079187.3	Q5T9L3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WLS	ENST00000262348.9 link	c.1393G>A	p.Val465Ile	missense_variant	Exon 11 of 12	1	NM_024911.7	ENSP00000262348.4		Q5T9L3-1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46628

AN:

151894

Hom.:

8130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.380

Gnomad AMR

AF:

0.361

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.342

GnomAD2 exomes

AF:

0.349

AC:

87538

AN:

251104

AF XY:

0.354

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.391

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.375

AC:

548025

AN:

1461474

Hom.:

105967

Cov.:

AF XY:

0.376

AC XY:

273379

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.133

AC:

4438

AN:

33458

American (AMR)

AF:

0.399

AC:

17851

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

10412

AN:

26118

East Asian (EAS)

AF:

0.142

AC:

5649

AN:

39694

South Asian (SAS)

AF:

0.364

AC:

31401

AN:

86240

European-Finnish (FIN)

AF:

0.327

AC:

17486

AN:

53402

Middle Eastern (MID)

AF:

0.346

AC:

1994

AN:

5766

European-Non Finnish (NFE)

AF:

0.394

AC:

437590

AN:

1111718

Other (OTH)

AF:

0.351

AC:

21204

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18074

36147

54221

72294

90368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13430

26860

40290

53720

67150

<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:

0.307

AC:

46653

AN:

152012

Hom.:

8137

Cov.:

AF XY:

0.305

AC XY:

22648

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.145

AC:

6032

AN:

41504

American (AMR)

AF:

0.361

AC:

5507

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1383

AN:

3470

East Asian (EAS)

AF:

0.146

AC:

755

AN:

5170

South Asian (SAS)

AF:

0.337

AC:

1618

AN:

4806

European-Finnish (FIN)

AF:

0.324

AC:

3412

AN:

10546

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.394

AC:

26771

AN:

67940

Other (OTH)

AF:

0.346

AC:

728

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1612

3224

4835

6447

8059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.367

Hom.:

48613

Bravo

AF:

0.303

TwinsUK

AF:

0.388

AC:

1440

ALSPAC

AF:

0.407

AC:

1568

ESP6500AA

AF:

0.149

AC:

658

ESP6500EA

AF:

0.396

AC:

3402

ExAC

AF:

0.345

AC:

41865

Asia WGS

AF:

0.231

AC:

802

AN:

3478

EpiCase

AF:

0.391

EpiControl

AF:

0.394

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.059

.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

.;N;.

PhyloP100

0.86

PrimateAI

Benign

0.48

PROVEAN

Benign

0.21

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.016

MPC

0.15

ClinPred

0.0098

GERP RS

4.5

Varity_R

0.024

gMVP

0.24

Mutation Taster

=98/2

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