14-100468021-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001161476.3(WDR25):​c.823G>T​(p.Val275Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

WDR25
NM_001161476.3 missense, splice_region

Scores

6
13
Splicing: ADA: 0.7659
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61
Variant links:
Genes affected
WDR25 (HGNC:21064): (WD repeat domain 25) This gene encodes a protein containing 7 WD repeats. WD repeats are approximately 30 to 40-amino acid domains containing several conserved residues, typically having a Tryptophan-Aspartic acid dipeptide (WD) at the C-terminal end. WD domains are involved in protein-protein interactions in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR25NM_001161476.3 linkuse as main transcriptc.823G>T p.Val275Leu missense_variant, splice_region_variant 3/7 ENST00000402312.8 NP_001154948.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR25ENST00000402312.8 linkuse as main transcriptc.823G>T p.Val275Leu missense_variant, splice_region_variant 3/72 NM_001161476.3 ENSP00000385540 P1Q64LD2-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249566
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135082
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460396
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726548
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

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 GeneticsApr 13, 2022The c.823G>T (p.V275L) alteration is located in exon 3 (coding exon 2) of the WDR25 gene. This alteration results from a G to T substitution at nucleotide position 823, causing the valine (V) at amino acid position 275 to be replaced by a leucine (L). 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
0.29
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.026
T;T;T;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
.;.;D;T
M_CAP
Benign
0.041
D
MetaRNN
Uncertain
0.46
T;T;T;D
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
-0.61
N;N;N;.
MutationTaster
Benign
0.68
D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-2.0
N;N;N;N
REVEL
Benign
0.16
Sift
Uncertain
0.021
D;D;D;D
Sift4G
Benign
0.077
T;T;T;D
Polyphen
0.098
B;B;B;P
Vest4
0.68
MutPred
0.57
Loss of methylation at K274 (P = 0.046);Loss of methylation at K274 (P = 0.046);Loss of methylation at K274 (P = 0.046);.;
MVP
0.10
MPC
0.11
ClinPred
0.23
T
GERP RS
3.2
Varity_R
0.10
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.77
dbscSNV1_RF
Benign
0.57
SpliceAI score (max)
0.030
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: rs755347286; hg19: chr14-100934358; API