chr5-111106140-G-A

Position:

chr5-111106140-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR36	NM_139281.3 linkuse as main transcript	c.1177G>A	p.Ala393Thr	missense_variant	11/23	ENST00000513710.4	NP_644810.2
WDR36	XM_047416729.1 linkuse as main transcript	c.1177G>A	p.Ala393Thr	missense_variant	11/21		XP_047272685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR36	ENST00000513710.4 linkuse as main transcript	c.1177G>A	p.Ala393Thr	missense_variant	11/23	1	NM_139281.3	ENSP00000424628	P1
WDR36	ENST00000505303.5 linkuse as main transcript	n.1313G>A		non_coding_transcript_exon_variant	11/15	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

GnomAD3 exomes

AF:

0.00826

AC:

2069

AN:

250400

Hom.:

AF XY:

0.0100

AC XY:

1353

AN XY:

135356

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 SAS exome

AF:

0.0397

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

Gnomad4 AFR exome

AF:

0.000901

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0396

Gnomad4 FIN exome

AF:

0.000993

Gnomad4 NFE exome

AF:

0.00407

Gnomad4 OTH exome

AF:

0.00720

GnomAD4 genome

AF:

0.00457

AC:

693

AN:

151604

Hom.:

Cov.:

AF XY:

0.00517

AC XY:

383

AN XY:

74104

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.00402

Gnomad4 ASJ

AF:

0.0191

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0421

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00451

Gnomad4 OTH

AF:

0.00714

Alfa

AF:

0.00510

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glaucoma 1, open angle, G

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Usher syndrome type 2C

Benign:1

Likely benign, criteria provided, single submitter

research

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

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

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

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;.

MutationTaster

Benign

0.98

A;A;A

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

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