X-49830500-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007003.4(PAGE4):c.72C>A(p.Phe24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,063,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000040 ( 0 hom. 26 hem. )

Failed GnomAD Quality Control

Consequence

PAGE4
NM_007003.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.635

Variant links:

Genes affected

PAGE4 (HGNC:4108): (PAGE family member 4) This gene is a member of the GAGE family. The GAGE genes are expressed in a variety of tumors and in some fetal and reproductive tissues. This gene is strongly expressed in prostate and prostate cancer. It is also expressed in other male and female reproductive tissues including testis, fallopian tube, uterus, and placenta, as well as in testicular cancer and uterine cancer. The protein encoded by this gene shares sequence similarity with other GAGE/PAGE proteins, and also belongs to a family of CT (cancer-testis) antigens. The protein may play a role in benign and malignant prostate diseases. A related pseudogene is located on chromosome 7. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

PAGE4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045734763).

BS2

High Hemizygotes in GnomAdExome4 at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE4	NM_007003.4 link	c.72C>A	p.Phe24Leu	missense_variant	Exon 2 of 5	ENST00000218068.7	NP_008934.1	O60829
PAGE4	NM_001318877.1 link	c.72C>A	p.Phe24Leu	missense_variant	Exon 2 of 5		NP_001305806.1	O60829
PAGE4	XM_047442678.1 link	c.72C>A	p.Phe24Leu	missense_variant	Exon 2 of 5		XP_047298634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAGE4	ENST00000218068.7 link	c.72C>A	p.Phe24Leu	missense_variant	Exon 2 of 5	1	NM_007003.4	ENSP00000218068.6	O60829
PAGE4	ENST00000376141.5 link	c.72C>A	p.Phe24Leu	missense_variant	Exon 2 of 5	5		ENSP00000365311.1	O60829
PAGE4	ENST00000478785.1 link	n.1153C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
PAGE4	ENST00000474146.1 link	n.-184C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111639

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33823

FAILED QC

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:

0.00

GnomAD3 exomes

AF:

0.0000660

AC:

AN:

166621

Hom.:

AF XY:

0.0000750

AC XY:

AN XY:

53325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000769

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1063099

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

331401

show subpopulations

Gnomad4 AFR exome

AF:

0.0000389

Gnomad4 AMR exome

AF:

0.0000876

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000681

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000246

Gnomad4 OTH exome

AF:

0.0000445

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111639

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33823

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:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.72C>A (p.F24L) alteration is located in exon 2 (coding exon 1) of the PAGE4 gene. This alteration results from a C to A substitution at nucleotide position 72, causing the phenylalanine (F) at amino acid position 24 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

0.62

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.3

DANN

Benign

0.52

DEOGEN2

Benign

0.0092

T;T

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.31

.;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.90

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.67

N;N

REVEL

Benign

0.014

Sift

Benign

0.52

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.097

B;B

Vest4

0.063

MutPred

0.37

Loss of catalytic residue at F24 (P = 0.0481);Loss of catalytic residue at F24 (P = 0.0481);

MVP

0.043

MPC

0.30

ClinPred

0.013

GERP RS

-1.4

Varity_R

0.045

gMVP

0.015

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.

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