chr5-111104342-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The NM_139281.3(WDR36):c.896A>G(p.Asn299Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,611,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

WDR36
NM_139281.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 9.21

Publications

18 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: Likely_benign. The variant received -3 ACMG points.

PP5

Variant 5-111104342-A-G is Pathogenic according to our data. Variant chr5-111104342-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1581.

BS2

High AC in GnomAd4 at 47 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR36	NM_139281.3 link	c.896A>G	p.Asn299Ser	missense_variant	Exon 8 of 23	ENST00000513710.4	NP_644810.2	Q8NI36
WDR36	XM_047416729.1 link	c.896A>G	p.Asn299Ser	missense_variant	Exon 8 of 21		XP_047272685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR36	ENST00000513710.4 link	c.896A>G	p.Asn299Ser	missense_variant	Exon 8 of 23	1	NM_139281.3	ENSP00000424628.3		A0A0A0MTB8
WDR36	ENST00000505303.5 link	n.1032A>G		non_coding_transcript_exon_variant	Exon 8 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.000310

AC:

AN:

151600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000502

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000243

AC:

AN:

250690

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000469

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000534

AC:

780

AN:

1460022

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

401

AN XY:

726304

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33384

American (AMR)

AF:

0.000134

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000665

AC:

738

AN:

1110586

Other (OTH)

AF:

0.000464

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000310

AC:

AN:

151600

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

74042

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41358

American (AMR)

AF:

0.000264

AC:

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000502

AC:

AN:

67720

Other (OTH)

AF:

0.000481

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000394

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, G

Pathogenic:2Uncertain:1

Mar 15, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.N299S in WDR36 (NM_139281.3) has been previously reported in affected members of a family in heterozygous state with primary open angle galucoma (Monemi et al). It has been submitted to ClinVar as Pathogenic based on the same family. It is alternatively also called Asn355Ser. The p.N299S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The asparagine residue at codon 299 of WDR36 is conserved in all mammalian species. The nucleotide c.896 in WDR36 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. This variant was observed in heterozygous state in her unaffected father. -

not provided

Uncertain:2

Nov 08, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in an individual with primary open-angle glaucoma in published literature, but familial segregation data was not included (Monemi et al., 2005); Identified in a patient with congenital corneal opacity and scleralization of the peripheral cornea who also harbored a variant in the MYOC gene; each variant was inherited from a different unaffected parent (Patel et al., 2019); Published functional studies demonstrate that N355S was significantly more potent in promoting thromboxane A2 receptor-mediated G-alpha-q signalling than wild-type WDR36, however, the significance of this result is uncertain (Cartier et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico splice predictor analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 19150991, 15677485, 21940795, 30653986) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;T

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

9.2

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.7

D;.;.

REVEL

Uncertain

0.45

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.96

MVP

0.71

MPC

0.087

ClinPred

0.82

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.35

Mutation Taster

=6/94

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over