X-49830500-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007003.4(PAGE4):​c.72C>G​(p.Phe24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,063,103 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: PAGE4 NM_007003.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062927395).

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>G	p.Phe24Leu	missense	Exon 2 of 5	NP_008934.1	O60829
	PAGE4	NM_001318877.1		c.72C>G	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>G	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000218068.6	O60829
	PAGE4	ENST00000376141.5	TSL:5	c.72C>G	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000365311.1	O60829
	PAGE4	ENST00000715210.1		c.72C>G	p.Phe24Leu	missense	Exon 2 of 5	ENSP00000520416.1	O60829

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.41e-7 AC: 1 AN: 1063103 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 331407

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25708

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000123 AC: 1 AN: 813769

Other (OTH) AF: 0.00 AC: 0 AN: 44954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

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	0.60
DANN	Benign	0.51
DEOGEN2	Benign	0.0092	T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.063	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	0.013
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		0.049	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;