X-49830500-C-A

Variant names:

• chrX-49830500-C-A
• rs782578883
• NM_007003.4:c.72C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.635
• Publications: 0 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.045734763).
• BS2: High Hemizygotes in GnomAdExome4 at 26 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007003.4. 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
	PAGE4	NM_007003.4	MANE Select	c.72C>A	p.Phe24Leu	missense	Exon 2 of 5	NP_008934.1	O60829
	PAGE4	NM_001318877.1		c.72C>A	p.Phe24Leu	missense	Exon 2 of 5	NP_001305806.1	O60829

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAGE4	ENST00000218068.7	TSL:1 MANE Select	c.72C>A	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000218068.6	O60829
	PAGE4	ENST00000376141.5	TSL:5	c.72C>A	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000365311.1	O60829
	PAGE4	ENST00000715210.1		c.72C>A	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000520416.1	O60829

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111639 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.0000660 AC: 11 AN: 166621 AF XY: 0.0000750

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 43 AN: 1063099 Hom.: 0 Cov.: 25 AF XY: 0.0000785 AC XY: 26 AN XY: 331401

African (AFR) AF: 0.0000389 AC: 1 AN: 25708

American (AMR) AF: 0.0000876 AC: 3 AN: 34234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19028

East Asian (EAS) AF: 0.00 AC: 0 AN: 29857

South Asian (SAS) AF: 0.000681 AC: 35 AN: 51373

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4053

European-Non Finnish (NFE) AF: 0.00000246 AC: 2 AN: 813765

Other (OTH) AF: 0.0000445 AC: 2 AN: 44954

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111639 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33823

African (AFR) AF: 0.00 AC: 0 AN: 30627

American (AMR) AF: 0.00 AC: 0 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53199

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.3
DANN	Benign	0.52
DEOGEN2	Benign	0.0092	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.64
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.014
Sift	Benign	0.52	T
Sift4G	Benign	0.39	T
Polyphen		0.097	B
Vest4		0.063
MutPred		0.37		Loss of catalytic residue at F24 (P = 0.0481)
MVP		0.043
MPC		0.30
ClinPred		0.013	T
GERP RS		-1.4
Varity_R		0.045
gMVP		0.015
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782578883; hg19: chrX-49595103;