10-120904047-A-G

Variant names:

• chr10-120904047-A-G
• rs144531702
• NM_018117.12:c.2932A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018117.12(WDR11):​c.2932A>G​(p.Lys978Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,453,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K978Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR11 NM_018117.12 missense, splice_region
• Scores: Splicing: ADA: 0.7132
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.58
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 14 with or without anosmia

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• intellectual developmental disorder, autosomal recessive 78

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105378519 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR11	NM_018117.12	c.2932A>G	p.Lys978Glu	missense_variant, splice_region_variant	Exon 24 of 29	ENST00000263461.11	NP_060587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR11	ENST00000263461.11	c.2932A>G	p.Lys978Glu	missense_variant, splice_region_variant	Exon 24 of 29	1	NM_018117.12	ENSP00000263461.5
WDR11	ENST00000497136.6	n.*1451A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 22 of 26	1		ENSP00000474595.1
WDR11	ENST00000605543.5	n.*1451A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 22	2		ENSP00000475076.1
WDR11	ENST00000497136.6	n.*1451A>G		3_prime_UTR_variant	Exon 22 of 26	1		ENSP00000474595.1
WDR11	ENST00000605543.5	n.*1451A>G		3_prime_UTR_variant	Exon 17 of 22	2		ENSP00000475076.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453340 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 723466

African (AFR) AF: 0.00 AC: 0 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105010

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.44
Sift	Benign	0.034	D
Sift4G	Uncertain	0.025	D
Polyphen		0.89	P
Vest4		0.68
MutPred		0.39		Loss of ubiquitination at K978 (P = 0.0103);
MVP		0.75
MPC		0.51
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.34
gMVP		0.40
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Benign	0.55
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

Other links and lift over

dbSNP: rs144531702; hg19: chr10-122663559;