5-111092571-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139281.3(WDR36):c.115C>G(p.Arg39Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: WDR36 NM_139281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.848

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21717969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3	c.115C>G	p.Arg39Gly	missense_variant	1/23	ENST00000513710.4
WDR36	XM_047416729.1	c.115C>G	p.Arg39Gly	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4	c.115C>G	p.Arg39Gly	missense_variant	1/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5	n.251C>G		non_coding_transcript_exon_variant	1/15	5
WDR36	ENST00000515784.1	n.225C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000924 AC: 23 AN: 249020 Hom.: 0 AF XY: 0.0000817 AC XY: 11 AN XY: 134678

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74512

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2022

This variant is present in population databases (rs772030651, gnomAD 0.03%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with glaucoma (PMID: 24825108, 32476818). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 95 of the WDR36 protein (p.Arg95Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;.
MutationTaster	Benign	0.88	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.90	N;.;.
REVEL	Benign	0.14
Sift4G	Benign	0.085	T;T;T
Polyphen		0.53	P;P;.
Vest4		0.46
MutPred		0.59		Loss of stability (P = 0.0181);Loss of stability (P = 0.0181);.;
MVP		0.49
MPC		0.037
ClinPred		0.33	T
GERP RS		5.0
Varity_R		0.63
gMVP		0.60

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: rs772030651; hg19: chr5-110428269; COSMIC: COSV72411394; COSMIC: COSV72411394;