Genetic Variant ENST00000289619.9:c.8C>T (chrX-55220607-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The ENST00000289619.9(PAGE5):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,196,841 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000030 ( 0 hom. 14 hem. )

Consequence

PAGE5
ENST00000289619.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0300

Variant links:

Genes affected

PAGE5 (HGNC:29992): (PAGE family member 5) This gene is a member of family of proteins that are expressed in a variety of tumors and in some fetal and reproductive tissues. The encoded protein may protect cells from programmed cell death. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found. [provided by RefSeq, Jan 2015]

PAGE5 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=0.042940766).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE5	NM_001013435.3 link	c.-9+155C>T		intron_variant	Intron 1 of 4	ENST00000374955.8	NP_001013453.1	Q96GU1-2
PAGE5	NM_130467.5 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 5		NP_569734.2	Q96GU1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAGE5	ENST00000289619.9 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 5	1		ENSP00000289619.5	Q96GU1-1
PAGE5	ENST00000374955.8 link	c.-9+155C>T		intron_variant	Intron 1 of 4	1	NM_001013435.3	ENSP00000364093.3	Q96GU1-2
PAGE5	ENST00000374952.1 link	c.-9+155C>T		intron_variant	Intron 1 of 4	5		ENSP00000364090.1	Q5JUL1

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111149

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33367

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

155226

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

48538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000802

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1085692

Hom.:

Cov.:

AF XY:

0.0000395

AC XY:

AN XY:

354736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000596

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000337

Gnomad4 SAS exome

AF:

0.0000962

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000287

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111149

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33367

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.000668

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.0000333

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8C>T (p.A3V) alteration is located in exon 1 (coding exon 1) of the PAGE5 gene. This alteration results from a C to T substitution at nucleotide position 8, causing the alanine (A) at amino acid position 3 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.68

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0079

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.34

M_CAP

Benign

0.0031

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PROVEAN

Benign

-0.58

REVEL

Benign

0.029

Sift

Uncertain

0.023

Sift4G

Benign

0.30

Polyphen

0.77

Vest4

0.024

MutPred

0.25

Gain of sheet (P = 0.1451);

MVP

0.14

MPC

0.16

ClinPred

0.053

GERP RS

-0.13

Varity_R

0.063

gMVP

0.010

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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