Genetic Variant PAGE5:p.Ala3Val (chrX-55220607-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_130467.5(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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000030 ( 0 hom. 14 hem. )

Consequence

PAGE5
NM_130467.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0300

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042940766).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130467.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAGE5	NM_001013435.3	MANE Select	c.-9+155C>T		intron	N/A	NP_001013453.1	Q96GU1-2
	PAGE5	NM_130467.5		c.8C>T	p.Ala3Val	missense	Exon 1 of 5	NP_569734.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAGE5	ENST00000289619.9	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 5	ENSP00000289619.5	Q96GU1-1
PAGE5	ENST00000374955.8	TSL:1 MANE Select	c.-9+155C>T		intron	N/A	ENSP00000364093.3	Q96GU1-2
PAGE5	ENST00000374952.1	TSL:5	c.-9+155C>T		intron	N/A	ENSP00000364090.1	Q5JUL1

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111149

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000322

AC:

AN:

155226

AF XY:

0.0000206

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 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

African (AFR)

AF:

0.00

AC:

AN:

26200

American (AMR)

AF:

0.0000596

AC:

AN:

33579

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19081

East Asian (EAS)

AF:

0.0000337

AC:

AN:

29632

South Asian (SAS)

AF:

0.0000962

AC:

AN:

51985

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4058

European-Non Finnish (NFE)

AF:

0.0000287

AC:

AN:

835849

Other (OTH)

AF:

0.0000219

AC:

AN:

45602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111149

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33367

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30506

American (AMR)

AF:

0.0000950

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.000283

AC:

AN:

3528

South Asian (SAS)

AF:

0.00

AC:

AN:

2604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52954

Other (OTH)

AF:

0.000668

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.0000333

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.68

(source)

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

PhyloP100

-0.030

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

PromoterAI

-0.44

Neutral

(source)

Varity_R

0.063

gMVP

0.010

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over