21-42850119-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018669.6(WDR4):​c.1169G>A​(p.Arg390Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,918 control chromosomes in the GnomAD database, including 30,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.24 ( 5538 hom., cov: 33)
Exomes 𝑓: 0.18 ( 24842 hom. )

Consequence

WDR4
NM_018669.6 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0760
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.3494492E-4).
BP6
Variant 21-42850119-C-T is Benign according to our data. Variant chr21-42850119-C-T is described in ClinVar as [Benign]. Clinvar id is 1234975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR4NM_018669.6 linkuse as main transcriptc.1169G>A p.Arg390Gln 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.1169G>A p.Arg390Gln missense_variant 11/111 NM_018669.6 ENSP00000381266.2 P57081-1
WDR4ENST00000330317.6 linkuse as main transcriptc.1169G>A p.Arg390Gln missense_variant 11/121 ENSP00000328671.2 P57081-1
WDR4ENST00000476326.5 linkuse as main transcriptn.1084G>A non_coding_transcript_exon_variant 11/111
WDR4ENST00000492742.5 linkuse as main transcriptn.1312G>A non_coding_transcript_exon_variant 11/112

Frequencies

GnomAD3 genomes
AF:
0.240
AC:
36517
AN:
152138
Hom.:
5536
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.440
Gnomad AMI
AF:
0.168
Gnomad AMR
AF:
0.169
Gnomad ASJ
AF:
0.196
Gnomad EAS
AF:
0.101
Gnomad SAS
AF:
0.201
Gnomad FIN
AF:
0.119
Gnomad MID
AF:
0.342
Gnomad NFE
AF:
0.170
Gnomad OTH
AF:
0.232
GnomAD3 exomes
AF:
0.181
AC:
45447
AN:
251140
Hom.:
5000
AF XY:
0.181
AC XY:
24548
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.454
Gnomad AMR exome
AF:
0.132
Gnomad ASJ exome
AF:
0.194
Gnomad EAS exome
AF:
0.110
Gnomad SAS exome
AF:
0.205
Gnomad FIN exome
AF:
0.126
Gnomad NFE exome
AF:
0.171
Gnomad OTH exome
AF:
0.179
GnomAD4 exome
AF:
0.177
AC:
258389
AN:
1461662
Hom.:
24842
Cov.:
32
AF XY:
0.178
AC XY:
129194
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.456
Gnomad4 AMR exome
AF:
0.133
Gnomad4 ASJ exome
AF:
0.195
Gnomad4 EAS exome
AF:
0.116
Gnomad4 SAS exome
AF:
0.208
Gnomad4 FIN exome
AF:
0.125
Gnomad4 NFE exome
AF:
0.170
Gnomad4 OTH exome
AF:
0.194
GnomAD4 genome
AF:
0.240
AC:
36547
AN:
152256
Hom.:
5538
Cov.:
33
AF XY:
0.234
AC XY:
17439
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.440
Gnomad4 AMR
AF:
0.169
Gnomad4 ASJ
AF:
0.196
Gnomad4 EAS
AF:
0.101
Gnomad4 SAS
AF:
0.200
Gnomad4 FIN
AF:
0.119
Gnomad4 NFE
AF:
0.170
Gnomad4 OTH
AF:
0.229
Alfa
AF:
0.192
Hom.:
5006
Bravo
AF:
0.253
TwinsUK
AF:
0.165
AC:
613
ALSPAC
AF:
0.174
AC:
670
ESP6500AA
AF:
0.436
AC:
1921
ESP6500EA
AF:
0.189
AC:
1626
ExAC
AF:
0.189
AC:
22890
Asia WGS
AF:
0.139
AC:
483
AN:
3478
EpiCase
AF:
0.184
EpiControl
AF:
0.178

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 05, 2021- -
Microcephaly, growth deficiency, seizures, and brain malformations Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Galloway-Mowat syndrome 6 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
0.23
DANN
Benign
0.60
DEOGEN2
Benign
0.011
T;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.078
N
LIST_S2
Benign
0.57
.;T
MetaRNN
Benign
0.00013
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.83
N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-0.62
N;N
REVEL
Benign
0.023
Sift
Benign
0.69
T;T
Sift4G
Benign
0.80
T;T
Polyphen
0.012
B;B
Vest4
0.055
MPC
0.023
ClinPred
0.00058
T
GERP RS
-1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.011
gMVP
0.19

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: rs6586250; hg19: chr21-44270229; COSMIC: COSV57733674; COSMIC: COSV57733674; API