Genetic Variant XAGE5:p.Leu108Val (chrX-52818208-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001386970.1(XAGE5):c.322C>G(p.Leu108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,210,100 control chromosomes in the GnomAD database, including 2 homozygotes. There are 10 hemizygotes in GnomAD. 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: 𝑓 0.00028 ( 2 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000022 ( 0 hom. 6 hem. )

Consequence

XAGE5
NM_001386970.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.34

Variant links:

Genes affected

XAGE5 (HGNC:30930): (X antigen family member 5) This gene is a member of the XAGE subfamily, which belongs to the GAGE family. The GAGE genes are expressed in a variety of tumors and in some fetal and reproductive tissues. The protein encoded by this gene shares a sequence similarity with other GAGE/PAGE proteins. Because of the expression pattern and the sequence similarity, this protein also belongs to a family of CT (cancer-testis) antigens. [provided by RefSeq, Jul 2008]

XAGE5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004954785).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XAGE5	NM_001386970.1 link	c.322C>G	p.Leu108Val	missense_variant	Exon 6 of 6	ENST00000375501.2	NP_001373899.1
XAGE5	NM_130775.3 link	c.322C>G	p.Leu108Val	missense_variant	Exon 5 of 5		NP_570131.1	Q8WWM1Q3SY49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
XAGE5	ENST00000375501.2 link	c.322C>G	p.Leu108Val	missense_variant	Exon 6 of 6	5	NM_001386970.1	ENSP00000364651.1	Q8WWM1
XAGE5	ENST00000375503.7 link	n.*250C>G		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000364653.3	Q3SY49
XAGE5	ENST00000375503.7 link	n.*250C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000364653.3	Q3SY49
XAGE5	ENST00000445860.2 link	n.325C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

112516

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34664

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0381

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:

0.0000937

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

182662

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

67270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000491

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1097584

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000276

AC:

AN:

112516

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34664

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000937

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000385

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322C>G (p.L108V) alteration is located in exon 5 (coding exon 4) of the XAGE5 gene. This alteration results from a C to G substitution at nucleotide position 322, causing the leucine (L) at amino acid position 108 to be replaced by a valine (V). 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

0.032

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-1.2

CADD

Benign

0.0070

DANN

Benign

0.094

DEOGEN2

Benign

0.012

T;T

FATHMM_MKL

Benign

0.00031

LIST_S2

Benign

0.34

T;.

M_CAP

Benign

0.00058

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.7

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.60

N;N

REVEL

Benign

0.0050

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.048

MVP

0.16

MPC

0.0028

ClinPred

0.021

GERP RS

-2.0

Varity_R

0.035

gMVP

0.0026

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over