NM_018117.12:c.2932A>C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_018117.12(WDR11):c.2932A>C(p.Lys978Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000128 in 1,605,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

WDR11
NM_018117.12 missense, splice_region

Scores

Splicing: ADA: 0.7491

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 6.58

Variant links:

Genes affected

WDR11 (HGNC:13831): (WD repeat domain 11) 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. This gene is located in the chromosome 10q25-26 region, which is frequently deleted in gliomas and tumors of other tissues, and is disrupted by the t(10;19) translocation rearrangement in glioblastoma cells. The gene location suggests that it is a candidate gene for the tumor suppressor locus. [provided by RefSeq, Jul 2008]

WDR11 links:

LOC105378519 (HGNC:):

LOC105378519 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31216636).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000131 (190/1453340) while in subpopulation MID AF= 0.00122 (7/5750). AF 95% confidence interval is 0.000571. There are 0 homozygotes in gnomad4_exome. There are 99 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR11	NM_018117.12 link	c.2932A>C	p.Lys978Gln	missense_variant, splice_region_variant	Exon 24 of 29	ENST00000263461.11	NP_060587.8	Q9BZH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR11	ENST00000263461.11 link	c.2932A>C	p.Lys978Gln	missense_variant, splice_region_variant	Exon 24 of 29	1	NM_018117.12	ENSP00000263461.5	Q9BZH6
WDR11	ENST00000497136.6 link	n.*1451A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 22 of 26	1		ENSP00000474595.1	S4R3P9
WDR11	ENST00000605543.5 link	n.*1451A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 22	2		ENSP00000475076.1	S4R451
WDR11	ENST00000497136.6 link	n.*1451A>C		3_prime_UTR_variant	Exon 22 of 26	1		ENSP00000474595.1	S4R3P9
WDR11	ENST00000605543.5 link	n.*1451A>C		3_prime_UTR_variant	Exon 17 of 22	2		ENSP00000475076.1	S4R451

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000184

AC:

AN:

249696

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000131

AC:

190

AN:

1453340

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

723466

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000144

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000105

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Mar 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20887964, 22035731) -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 20, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 978 of the WDR11 protein (p.Lys978Gln). This variant is present in population databases (rs144531702, gnomAD 0.03%). This missense change has been observed in individual(s) with WDR11-related conditions (PMID: 20887964). ClinVar contains an entry for this variant (Variation ID: 68841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

not specified

Uncertain:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WDR11 c.2932A>C (p.Lys978Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 249696 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WDR11 causing WDR11-Related Disorders, allowing no conclusion about variant significance. c.2932A>C has been reported in the literature in three heterozygous individuals affected with WDR11-Related Disorders; however, this variant has also been detected in two control subjects (Kim_2010, Federici_2022). These report(s) do not provide unequivocal conclusions about association of the variant with WDR11-Related Disorders. One experimental study has shown that this variant does not affect splicing in an in vitro exon trapping assay (Kim_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36531499, 20887964). ClinVar contains an entry for this variant (Variation ID: 68841). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.062

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.41

REVEL

Uncertain

0.39

Sift

Benign

0.19

Sift4G

Uncertain

0.041

Polyphen

0.97

Vest4

0.58

MVP

0.75

MPC

0.36

ClinPred

0.091

GERP RS

5.9

Varity_R

0.24

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.75

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.010

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