rs35703638

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139281.3(WDR36):c.1177G>A(p.Ala393Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0061 in 1,609,244 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 140 hom. )

Consequence

WDR36
NM_139281.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 2.25

Publications

21 publications found

Variant links:

Genes affected

WDR36 (HGNC:30696): (WD repeat domain 36) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations in this gene have been associated with adult-onset primary open-angle glaucoma (POAG). [provided by RefSeq, Jul 2008]

WDR36 Gene-Disease associations (from GenCC):

glaucoma 1, open angle, G
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

WDR36 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058906674).

BP6

Variant 5-111106140-G-A is Benign according to our data. Variant chr5-111106140-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00457 (693/151604) while in subpopulation SAS AF = 0.0421 (203/4820). AF 95% confidence interval is 0.0374. There are 7 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 693 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR36	NM_139281.3 link	c.1177G>A	p.Ala393Thr	missense_variant	Exon 11 of 23	ENST00000513710.4	NP_644810.2	Q8NI36
WDR36	XM_047416729.1 link	c.1177G>A	p.Ala393Thr	missense_variant	Exon 11 of 21		XP_047272685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR36	ENST00000513710.4 link	c.1177G>A	p.Ala393Thr	missense_variant	Exon 11 of 23	1	NM_139281.3	ENSP00000424628.3		A0A0A0MTB8
WDR36	ENST00000505303.5 link	n.1313G>A		non_coding_transcript_exon_variant	Exon 11 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

692

AN:

151486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00403

Gnomad ASJ

AF:

0.0191

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0419

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.00721

GnomAD2 exomes

AF:

0.00826

AC:

2069

AN:

250400

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00459

Gnomad OTH exome

AF:

0.00885

GnomAD4 exome

AF:

0.00626

AC:

9125

AN:

1457640

Hom.:

140

Cov.:

AF XY:

0.00737

AC XY:

5345

AN XY:

725190

show subpopulations

African (AFR)

AF:

0.000901

AC:

AN:

33300

American (AMR)

AF:

0.00211

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

481

AN:

25978

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39546

South Asian (SAS)

AF:

0.0396

AC:

3407

AN:

86136

European-Finnish (FIN)

AF:

0.000993

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.0190

AC:

109

AN:

5740

European-Non Finnish (NFE)

AF:

0.00407

AC:

4517

AN:

1108894

Other (OTH)

AF:

0.00720

AC:

433

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

481

961

1442

1922

2403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00457

AC:

693

AN:

151604

Hom.:

Cov.:

AF XY:

0.00517

AC XY:

383

AN XY:

74104

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

41486

American (AMR)

AF:

0.00402

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

AN:

3448

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0421

AC:

203

AN:

4820

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00451

AC:

305

AN:

67588

Other (OTH)

AF:

0.00714

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00512

Hom.:

Bravo

AF:

0.00384

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00846

AC:

1027

Asia WGS

AF:

0.0120

AC:

AN:

3476

EpiCase

AF:

0.00612

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Glaucoma 1, open angle, G

Uncertain:1

Jan 01, 2008

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Usher syndrome type 2C

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ala449Thr variant in WDR36 has been identified in at least 2 individuals with primary open angle glaucoma (PMID: 15677485, 19150991, 22995991). However, this variant has also been described as a benign polymorphism that does not segregate with disease (PMID: 18172102), and has been identified in >3% of South Asian chromosomes and 31 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Models in yeast suggest that this variant does not cause primary open angle glaucoma (PMID: 19150991). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for primary open angle glaucoma. -

WDR36-related disorder

Benign:1

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

.;D;D

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

2.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.0

N;.;.

REVEL

Benign

0.26

Sift4G

Benign

0.17

T;T;T

Polyphen

0.72

P;P;.

Vest4

0.23

MVP

0.92

MPC

0.030

ClinPred

0.0051

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.36

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over