rs144440500

Variant names:

• chr10-120871218-G-A
• rs144440500
• NM_018117.12:c.1343G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_Moderate BP4_Strong BS1_Supporting BS2

The NM_018117.12(WDR11):​c.1343G>A​(p.Arg448Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000312 in 1,613,986 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: WDR11 NM_018117.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.06

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PS1: Transcript NM_018117.12 (WDR11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.061038584).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000171 (26/152110) while in subpopulation NFE AF= 0.000323 (22/68012). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR11	NM_018117.12	c.1343G>A	p.Arg448Gln	missense_variant	Exon 10 of 29	ENST00000263461.11	NP_060587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR11	ENST00000263461.11	c.1343G>A	p.Arg448Gln	missense_variant	Exon 10 of 29	1	NM_018117.12	ENSP00000263461.5
WDR11	ENST00000497136.6	n.462G>A		non_coding_transcript_exon_variant	Exon 8 of 26	1		ENSP00000474595.1
WDR11	ENST00000605543.5	n.167-17G>A		intron_variant	Intron 2 of 21	2		ENSP00000475076.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

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: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251440 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135892

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000327 AC: 478 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 235 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000394

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74314

Gnomad4 AFR AF: 0.0000966

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: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 448 of the WDR11 protein (p.Arg448Gln). This variant is present in population databases (rs144440500, gnomAD 0.03%). This missense change has been observed in individuals with idiopathic hypogonadotropic hypogonadism (PMID: 20887964; Invitae). ClinVar contains an entry for this variant (Variation ID: 68839). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects WDR11 function (PMID: 29263200). This variant disrupts the p.Arg448 amino acid residue in WDR11. Other variant(s) that disrupt this residue have been observed in individuals with WDR11-related conditions (PMID: 20887964, 29419413), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.32
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-2.1	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.060	N;.
REVEL	Uncertain	0.37
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.70
MVP		0.52
MPC		0.35
ClinPred		0.037	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144440500; hg19: chr10-122630730;