Genetic Variant PAGE4:p.Pro53Ser (chrX-49831075-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_007003.4(PAGE4):c.157C>T(p.Pro53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PAGE4
NM_007003.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.100

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:

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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=0.047038376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE4	NM_007003.4 link	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 5	ENST00000218068.7	NP_008934.1	O60829
PAGE4	NM_001318877.1 link	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 5		NP_001305806.1	O60829
PAGE4	XM_047442678.1 link	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 5		XP_047298634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAGE4	ENST00000218068.7 link	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 5	1	NM_007003.4	ENSP00000218068.6	O60829
PAGE4	ENST00000376141.5 link	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 5	5		ENSP00000365311.1	O60829
PAGE4	ENST00000474146.1 link	n.199C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
PAGE4	ENST00000478785.1 link	n.1238C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1048495

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

323069

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157C>T (p.P53S) alteration is located in exon 3 (coding exon 2) of the PAGE4 gene. This alteration results from a C to T substitution at nucleotide position 157, causing the proline (P) at amino acid position 53 to be replaced by a serine (S). 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

0.087

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.052

DANN

Benign

0.36

DEOGEN2

Benign

0.0020

T;T

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.44

.;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.55

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.16

N;N

REVEL

Benign

0.010

Sift

Benign

0.70

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0030

B;B

Vest4

0.14

MutPred

0.22

Loss of catalytic residue at P52 (P = 0.012);Loss of catalytic residue at P52 (P = 0.012);

MVP

0.043

MPC

0.28

ClinPred

0.027

GERP RS

0.34

Varity_R

0.023

gMVP

0.013

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over