rs34661294

chr5-111111204-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_139281.3(WDR36):c.1642A>G(p.Ile548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,611,944 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (10 hom.)
• Consequence: WDR36 NM_139281.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.33

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007596582).
• BP6: Variant 5-111111204-A-G is Benign according to our data. Variant chr5-111111204-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350319.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr5-111111204-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00525 (797/151742) while in subpopulation AFR AF= 0.018 (749/41506). AF 95% confidence interval is 0.017. There are 15 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3	c.1642A>G	p.Ile548Val	missense_variant	15/23	ENST00000513710.4
WDR36	XM_047416729.1	c.1642A>G	p.Ile548Val	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4	c.1642A>G	p.Ile548Val	missense_variant	15/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5	n.1778A>G		non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 796 AN: 151624 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00136 AC: 342 AN: 251162 Hom.: 4 AF XY: 0.000936 AC XY: 127 AN XY: 135756

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1460202 Hom.: 10 Cov.: 31 AF XY: 0.000449 AC XY: 326 AN XY: 726400

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.00525 AC: 797 AN: 151742 Hom.: 15 Cov.: 32 AF XY: 0.00531 AC XY: 394 AN XY: 74188

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00266 Hom.: 0

Bravo AF: 0.00623

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary open angle glaucoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.77	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N;.;.
REVEL	Uncertain	0.32
Sift4G	Benign	0.54	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.75
MVP		0.55
MPC		0.027
ClinPred		0.0051	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.29

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: rs34661294; hg19: chr5-110446903;