chr2-189466557-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032168.3(WDR75):ā€‹c.1422A>Gā€‹(p.Ile474Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

WDR75
NM_032168.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.862
Variant links:
Genes affected
WDR75 (HGNC:25725): (WD repeat domain 75) Enables RNA binding activity. Involved in positive regulation of rRNA processing and positive regulation of transcription by RNA polymerase I. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046172976).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WDR75NM_032168.3 linkuse as main transcriptc.1422A>G p.Ile474Met missense_variant 13/21 ENST00000314761.9
WDR75NM_001303096.2 linkuse as main transcriptc.1230A>G p.Ile410Met missense_variant 14/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WDR75ENST00000314761.9 linkuse as main transcriptc.1422A>G p.Ile474Met missense_variant 13/211 NM_032168.3 P1
WDR75ENST00000427960.5 linkuse as main transcriptc.*2786A>G 3_prime_UTR_variant, NMD_transcript_variant 13/211
WDR75ENST00000436347.5 linkuse as main transcriptc.*1186A>G 3_prime_UTR_variant, NMD_transcript_variant 14/222

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152182
Hom.:
0
Cov.:
32
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:
0.000192
Gnomad SAS
AF:
0.000413
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250024
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135142
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000655
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1460594
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726584
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2023The c.1422A>G (p.I474M) alteration is located in exon 13 (coding exon 13) of the WDR75 gene. This alteration results from a A to G substitution at nucleotide position 1422, causing the isoleucine (I) at amino acid position 474 to be replaced by a methionine (M). 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
0.069
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
15
DANN
Benign
0.96
DEOGEN2
Benign
0.044
T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.046
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
0.70
N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
0.050
N
REVEL
Benign
0.056
Sift
Benign
0.17
T
Sift4G
Benign
0.16
T
Polyphen
0.0
B
Vest4
0.15
MutPred
0.54
Loss of ubiquitination at K471 (P = 0.0834);
MVP
0.068
MPC
0.16
ClinPred
0.051
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.034
gMVP
0.23

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: rs370434777; hg19: chr2-190331283; API