X-49830999-C-T

Variant names:

• chrX-49830999-C-T
• rs78248125
• NM_007003.4:c.81C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_007003.4(PAGE4):​c.81C>T​(p.Pro27Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,178,481 control chromosomes in the GnomAD database, including 17 homozygotes. There are 384 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., 206 hem., cov: 23)
  • Exomes 𝑓: 0.00067 (9 hom. 178 hem.)
• Consequence: PAGE4 NM_007003.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.170
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-49830999-C-T is Benign according to our data. Variant chrX-49830999-C-T is described in ClinVar as Benign. ClinVar VariationId is 710171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00717 (798/111324) while in subpopulation AFR AF = 0.0253 (776/30625). AF 95% confidence interval is 0.0239. There are 8 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.81C>T	p.Pro27Pro	splice_region synonymous	Exon 3 of 5	NP_008934.1	O60829
	PAGE4	NM_001318877.1		c.81C>T	p.Pro27Pro	splice_region synonymous	Exon 3 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.81C>T	p.Pro27Pro	splice_region synonymous	Exon 3 of 5	ENSP00000218068.6	O60829
	PAGE4	ENST00000376141.5	TSL:5	c.81C>T	p.Pro27Pro	splice_region synonymous	Exon 3 of 5	ENSP00000365311.1	O60829
	PAGE4	ENST00000715210.1		c.81C>T	p.Pro27Pro	splice_region synonymous	Exon 3 of 5	ENSP00000520416.1	O60829

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 796 AN: 111274 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000565

Gnomad OTH AF: 0.00401

GnomAD2 exomes AF: 0.00180 AC: 260 AN: 144594 AF XY: 0.000715

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.000801

GnomAD4 exome AF: 0.000672 AC: 717 AN: 1067157 Hom.: 9 Cov.: 26 AF XY: 0.000523 AC XY: 178 AN XY: 340473

African (AFR) AF: 0.0236 AC: 608 AN: 25762

American (AMR) AF: 0.000869 AC: 28 AN: 32225

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18776

East Asian (EAS) AF: 0.0000338 AC: 1 AN: 29599

South Asian (SAS) AF: 0.000178 AC: 9 AN: 50490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39332

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4088

European-Non Finnish (NFE) AF: 0.0000134 AC: 11 AN: 821880

Other (OTH) AF: 0.00131 AC: 59 AN: 45005

GnomAD4 genome AF: 0.00717 AC: 798 AN: 111324 Hom.: 8 Cov.: 23 AF XY: 0.00614 AC XY: 206 AN XY: 33554

African (AFR) AF: 0.0253 AC: 776 AN: 30625

American (AMR) AF: 0.00124 AC: 13 AN: 10458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53086

Other (OTH) AF: 0.00397 AC: 6 AN: 1513

Alfa AF: 0.000524 Hom.: 4

Bravo AF: 0.00790

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.55
DANN	Benign	0.17
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78248125; hg19: chrX-49595602;