rs118204022

Positions:

chr5-111104342-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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:2

Conservation

PhyloP100: 9.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 1581.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr5-111104342-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3 linkuse as main transcript	c.896A>G	p.Asn299Ser	missense_variant	8/23	ENST00000513710.4
WDR36	XM_047416729.1 linkuse as main transcript	c.896A>G	p.Asn299Ser	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4 linkuse as main transcript	c.896A>G	p.Asn299Ser	missense_variant	8/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5 linkuse as main transcript	n.1032A>G		non_coding_transcript_exon_variant	8/15	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

GnomAD3 exomes

AF:

0.000243

AC:

AN:

250690

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135470

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 SAS 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

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000665

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000310

AC:

AN:

151600

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.000264

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000502

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.000405

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:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, G

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2019

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) -

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

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;.

MutationTaster

Benign

1.0

A;A;A

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over