X-49830488-T-A

Variant names:

• chrX-49830488-T-A
• NM_007003.4:c.60T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007003.4(PAGE4):​c.60T>A​(p.Asp20Glu) 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)
• Consequence: PAGE4 NM_007003.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.686

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

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=0.051508337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAGE4	NM_007003.4	c.60T>A	p.Asp20Glu	missense_variant	Exon 2 of 5	ENST00000218068.7	NP_008934.1
PAGE4	NM_001318877.1	c.60T>A	p.Asp20Glu	missense_variant	Exon 2 of 5		NP_001305806.1
PAGE4	XM_047442678.1	c.60T>A	p.Asp20Glu	missense_variant	Exon 2 of 5		XP_047298634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAGE4	ENST00000218068.7	c.60T>A	p.Asp20Glu	missense_variant	Exon 2 of 5	1	NM_007003.4	ENSP00000218068.6
PAGE4	ENST00000376141.5	c.60T>A	p.Asp20Glu	missense_variant	Exon 2 of 5	5		ENSP00000365311.1
PAGE4	ENST00000478785.1	n.1141T>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
PAGE4	ENST00000474146.1	n.-196T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.60T>A (p.D20E) alteration is located in exon 2 (coding exon 1) of the PAGE4 gene. This alteration results from a T to A substitution at nucleotide position 60, causing the aspartic acid (D) at amino acid position 20 to be replaced by a glutamic acid (E). 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	-0.63	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.037
DANN	Benign	0.45
DEOGEN2	Benign	0.0073	T;T
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.65	P;P
Vest4		0.073
MutPred		0.35		Gain of catalytic residue at D20 (P = 0.0558);Gain of catalytic residue at D20 (P = 0.0558);
MVP		0.043
MPC		0.34
ClinPred		0.13	T
GERP RS		-1.9
Varity_R		0.053
gMVP		0.0030

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.

Other links and lift over

hg19: chrX-49595091;