chrX-154478391-G-A

Position:

• chrX-154478391-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006014.5(LAGE3):​c.209C>T​(p.Pro70Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LAGE3 NM_006014.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

Genes affected

LAGE3 (HGNC:26058): (L antigen family member 3) This gene belongs to the ESO/LAGE gene family, members of which are clustered together on chromosome Xq28, and have similar exon-intron structures. Unlike the other family members which are normally expressed only in testis and activated in a wide range of human tumors, this gene is ubiquitously expressed in somatic tissues. The latter, combined with the finding that it is highly conserved in mouse and rat, suggests that the encoded protein is functionally important. An intronless pseudogene with high sequence similarity to this gene is located on chromosome 9. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3636074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAGE3	NM_006014.5	c.209C>T	p.Pro70Leu	missense_variant	2/3	ENST00000357360.5	NP_006005.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAGE3	ENST00000357360.5	c.209C>T	p.Pro70Leu	missense_variant	2/3	1	NM_006014.5	ENSP00000349923.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galloway-Mowat syndrome 2, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense variant c.209C>T(p.Pro70Leu) in LAGE3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.209C>T variant is absent in gnomAD Exomes. The amino acid Proline at position 70 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen, SIFT and MutationTaster) predicts conflicting evidence on protein structure and function for this variant.The amino acid change p.Pro70Leu in LAGE3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.095
Sift	Benign	0.22	T
Sift4G	Uncertain	0.017	D
Polyphen		0.45	P
Vest4		0.33
MutPred		0.50		Loss of disorder (P = 0.0217);
MVP		0.74
MPC		0.69
ClinPred		0.84	D
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.87

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-153706730;