Genetic Variant PAGE1:p.Arg11His (chrX-49694739-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003785.4(PAGE1):c.32G>A(p.Arg11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,197,241 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 4 hem. )

Consequence

PAGE1
NM_003785.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.259

Variant links:

Genes affected

PAGE1 (HGNC:4107): (PAGE family member 1) This gene belongs to a family of genes that are expressed in a variety of tumors but not in normal tissues, except for the testis. Unlike the other gene family members, this gene does not encode an antigenic peptide. Nothing is presently known about the function of this protein. [provided by RefSeq, Jul 2008]

PAGE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.114269316).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE1	NM_003785.4 link	c.32G>A	p.Arg11His	missense_variant	Exon 2 of 6	ENST00000376150.4	NP_003776.2	O75459
PAGE1	XM_011543998.3 link	c.32G>A	p.Arg11His	missense_variant	Exon 2 of 6		XP_011542300.1	O75459

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAGE1	ENST00000376150.4 link	c.32G>A	p.Arg11His	missense_variant	Exon 2 of 6	1	NM_003785.4	ENSP00000365320.3		O75459

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112167

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34347

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:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000224

AC:

AN:

178298

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

62922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000581

Gnomad FIN exome

AF:

0.0000628

Gnomad NFE exome

AF:

0.0000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1085074

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

351444

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000860

Gnomad4 ASJ exome

AF:

0.0000519

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000190

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112167

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34347

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:

0.000165

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32G>A (p.R11H) alteration is located in exon 2 (coding exon 1) of the PAGE1 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the arginine (R) at amino acid position 11 to be replaced by a histidine (H). 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

0.22

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.4

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0017

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.44

M_CAP

Benign

0.0017

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

0.31

REVEL

Benign

0.061

Sift

Benign

0.31

Sift4G

Benign

0.095

Polyphen

0.99

Vest4

0.045

MutPred

0.50

Loss of stability (P = 0.0387);

MVP

0.030

MPC

0.34

ClinPred

0.12

GERP RS

0.65

Varity_R

0.034

gMVP

0.016

Splicing

Name

Calibrated prediction

Score

Prediction

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.

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