rs116529882

chr5-111110280-G-Achr5-111110280-G-C

Variant summary

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

The NM_139281.3(WDR36):c.1418G>A(p.Arg473Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,610,592 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: WDR36 NM_139281.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3	c.1418G>A	p.Arg473Gln	missense_variant	13/23	ENST00000513710.4
WDR36	XM_047416729.1	c.1418G>A	p.Arg473Gln	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4	c.1418G>A	p.Arg473Gln	missense_variant	13/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5	n.1554G>A		non_coding_transcript_exon_variant	13/15	5

Frequencies

GnomAD3 genomes AF: 0.000872 AC: 132 AN: 151326 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000397

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: 0.00169

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000750 AC: 188 AN: 250698 Hom.: 1 AF XY: 0.000679 AC XY: 92 AN XY: 135508

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00137 AC: 1997 AN: 1459150 Hom.: 3 Cov.: 31 AF XY: 0.00131 AC XY: 954 AN XY: 725908

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000872 AC: 132 AN: 151442 Hom.: 0 Cov.: 32 AF XY: 0.000743 AC XY: 55 AN XY: 74036

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00169

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 1, open angle, G Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2005

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 529 of the WDR36 protein (p.Arg529Gln). This variant is present in population databases (rs116529882, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of WDR36-related conditions (PMID: 15677485, 16723468, 17563723). ClinVar contains an entry for this variant (Variation ID: 1583). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Pathogenic	0.83
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MVP		0.94
MPC		0.24
ClinPred		0.20	T
GERP RS		5.3
Varity_R		0.69
gMVP		0.63

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

Other links and lift over

dbSNP: rs116529882; hg19: chr5-110445979;