21-42850120-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_018669.6(WDR4):​c.1168C>T​(p.Arg390Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

WDR4
NM_018669.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.264
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 -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10166624).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000301 (44/1461698) while in subpopulation SAS AF= 0.000313 (27/86238). AF 95% confidence interval is 0.000221. There are 0 homozygotes in gnomad4_exome. There are 26 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.1168C>T p.Arg390Trp 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.1168C>T p.Arg390Trp missense_variant 11/111 NM_018669.6 ENSP00000381266.2 P57081-1
WDR4ENST00000330317.6 linkuse as main transcriptc.1168C>T p.Arg390Trp missense_variant 11/121 ENSP00000328671.2 P57081-1
WDR4ENST00000476326.5 linkuse as main transcriptn.1083C>T non_coding_transcript_exon_variant 11/111
WDR4ENST00000492742.5 linkuse as main transcriptn.1311C>T non_coding_transcript_exon_variant 11/112

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000518
AC:
13
AN:
251206
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135824
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.0000926
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461698
Hom.:
0
Cov.:
32
AF XY:
0.0000358
AC XY:
26
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000313
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 25, 2022The c.1168C>T (p.R390W) alteration is located in exon 11 (coding exon 11) of the WDR4 gene. This alteration results from a C to T substitution at nucleotide position 1168, causing the arginine (R) at amino acid position 390 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 08, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with WDR4-related conditions. This variant is present in population databases (rs375403604, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 390 of the WDR4 protein (p.Arg390Trp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
14
DANN
Uncertain
1.0
DEOGEN2
Benign
0.032
T;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.63
.;T
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.0
L;L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-2.3
N;N
REVEL
Benign
0.13
Sift
Benign
0.030
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.99
D;D
Vest4
0.18
MVP
0.65
MPC
0.097
ClinPred
0.11
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.034
gMVP
0.32

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: rs375403604; hg19: chr21-44270230; API