10-120904047-A-C

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

1
9
9
Splicing: ADA: 0.7491
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O: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]

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/exons MANE Protein UniProt
WDR11NM_018117.12 linkuse as main transcriptc.2932A>C p.Lys978Gln missense_variant, splice_region_variant 24/29 ENST00000263461.11 NP_060587.8
LOC105378519XR_001747609.2 linkuse as main transcriptn.541-1705T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR11ENST00000263461.11 linkuse as main transcriptc.2932A>C p.Lys978Gln missense_variant, splice_region_variant 24/291 NM_018117.12 ENSP00000263461 P1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152180
Hom.:
0
Cov.:
33
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:
46
AN:
249696
Hom.:
0
AF XY:
0.000207
AC XY:
28
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.:
0
Cov.:
28
AF XY:
0.000137
AC XY:
99
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:
16
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
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.:
0
Bravo
AF:
0.000132
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000198
AC:
24
EpiCase
AF:
0.000218
EpiControl
AF:
0.000652

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3Other:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 15, 2023This 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 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 21, 2024In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20887964, 22035731) -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 20, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.094
T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.31
T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-0.41
N
REVEL
Uncertain
0.39
Sift
Benign
0.19
T
Sift4G
Uncertain
0.041
D
Polyphen
0.97
D
Vest4
0.58
MVP
0.75
MPC
0.36
ClinPred
0.091
T
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.

Other links and lift over

dbSNP: rs144531702; hg19: chr10-122663559; COSMIC: COSV54788431; COSMIC: COSV54788431; API