Genetic Variant WDR75:p.Phe96Leu (chr2-189451810-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032168.3(WDR75):c.288C>G(p.Phe96Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Consequence

WDR75
NM_032168.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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]

WDR75 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16626951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR75	NM_032168.3 link	c.288C>G	p.Phe96Leu	missense_variant	Exon 4 of 21	ENST00000314761.9	NP_115544.1	Q8IWA0
WDR75	NM_001303096.2 link	c.96C>G	p.Phe32Leu	missense_variant	Exon 5 of 22		NP_001290025.1	Q8IWA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR75	ENST00000314761.9 link	c.288C>G	p.Phe96Leu	missense_variant	Exon 4 of 21	1	NM_032168.3	ENSP00000314193.4		Q8IWA0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.288C>G (p.F96L) alteration is located in exon 4 (coding exon 4) of the WDR75 gene. This alteration results from a C to G substitution at nucleotide position 288, causing the phenylalanine (F) at amino acid position 96 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

Pathogenic

0.80

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.85

M_CAP

Benign

0.0075

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.14

Sift

Uncertain

0.011

Sift4G

Uncertain

0.018

Polyphen

0.93

Vest4

0.43

MutPred

0.43

Gain of ubiquitination at K94 (P = 0.0804);

MVP

0.11

MPC

0.27

ClinPred

0.91

GERP RS

3.3

Varity_R

0.18

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over