21-42850138-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_018669.6(WDR4):​c.1150G>A​(p.Glu384Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

WDR4
NM_018669.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0860
Variant links:
Genes affected
WDR4 (HGNC:12756): (WD repeat domain 4) 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 excluded as a candidate for a form of nonsyndromic deafness (DFNB10), but is still a candidate for other disorders mapped to 21q22.3 as well as for the development of Down syndrome phenotypes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.045400172).
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000315 (46/1461754) while in subpopulation EAS AF= 0.000529 (21/39690). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR4NM_018669.6 linkuse as main transcriptc.1150G>A p.Glu384Lys missense_variant 11/11 ENST00000398208.3 NP_061139.2 P57081-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR4ENST00000398208.3 linkuse as main transcriptc.1150G>A p.Glu384Lys missense_variant 11/111 NM_018669.6 ENSP00000381266.2 P57081-1
WDR4ENST00000330317.6 linkuse as main transcriptc.1150G>A p.Glu384Lys missense_variant 11/121 ENSP00000328671.2 P57081-1
WDR4ENST00000476326.5 linkuse as main transcriptn.1065G>A non_coding_transcript_exon_variant 11/111
WDR4ENST00000492742.5 linkuse as main transcriptn.1293G>A non_coding_transcript_exon_variant 11/112

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152258
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251256
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
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:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461754
Hom.:
0
Cov.:
32
AF XY:
0.0000316
AC XY:
23
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000529
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 04, 2022The c.1150G>A (p.E384K) alteration is located in exon 11 (coding exon 11) of the WDR4 gene. This alteration results from a G to A substitution at nucleotide position 1150, causing the glutamic acid (E) at amino acid position 384 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
6.5
DANN
Uncertain
0.98
DEOGEN2
Benign
0.016
T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.77
.;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.045
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.43
N;N
REVEL
Benign
0.034
Sift
Benign
0.21
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.0020
B;B
Vest4
0.12
MutPred
0.26
Gain of methylation at E384 (P = 0.0143);Gain of methylation at E384 (P = 0.0143);
MVP
0.28
MPC
0.023
ClinPred
0.024
T
GERP RS
1.6
Varity_R
0.027
gMVP
0.14

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201837743; hg19: chr21-44270248; API