Genetic Variant WDR77:p.Pro265Ala (chr1-111442660-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024102.4(WDR77):c.793C>G(p.Pro265Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

WDR77
NM_024102.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.888

Publications

0 publications found

Variant links:

Genes affected

WDR77 (HGNC:29652): (WD repeat domain 77) The protein encoded by this gene is an androgen receptor coactivator that forms a complex with protein arginine methyltransferase 5, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins. The encoded protein may be involved in the early stages of prostate cancer, with most of the protein being nuclear-localized in benign cells but cytoplasmic in cancer cells. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

WDR77 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19648433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR77	NM_024102.4 link	c.793C>G	p.Pro265Ala	missense_variant	Exon 8 of 10	ENST00000235090.10	NP_077007.1	Q9BQA1-1A0A024R0H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR77	ENST00000235090.10 link	c.793C>G	p.Pro265Ala	missense_variant	Exon 8 of 10	1	NM_024102.4	ENSP00000235090.5	Q9BQA1-1
WDR77	ENST00000449340.1 link	c.601C>G	p.Pro201Ala	missense_variant	Exon 7 of 9	5		ENSP00000409300.1	H0Y711
WDR77	ENST00000497278.5 link	n.448C>G		non_coding_transcript_exon_variant	Exon 6 of 9	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422010

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700958

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32534

American (AMR)

AF:

0.00

AC:

AN:

41558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38708

South Asian (SAS)

AF:

0.00

AC:

AN:

80138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086968

Other (OTH)

AF:

0.00

AC:

AN:

58528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.793C>G (p.P265A) alteration is located in exon 8 (coding exon 8) of the WDR77 gene. This alteration results from a C to G substitution at nucleotide position 793, causing the proline (P) at amino acid position 265 to be replaced by an alanine (A). 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

0.074

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.39

Eigen

Benign

-0.098

Eigen_PC

Benign

0.091

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.83

M_CAP

Benign

0.0071

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.89

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.051

Sift

Benign

0.15

Sift4G

Benign

0.57

Polyphen

0.0070

Vest4

0.20

MutPred

0.46

Gain of catalytic residue at P265 (P = 0.0227);

MVP

0.66

MPC

0.50

ClinPred

0.29

GERP RS

3.9

Varity_R

0.17

gMVP

0.14

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over