chrX-154478298-C-T

Variant names:

• chrX-154478298-C-T
• rs1037257365
• NM_006014.5:c.302G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006014.5(LAGE3):​c.302G>A​(p.Gly101Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,391 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: LAGE3 NM_006014.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.838
• Publications: 0 publications found

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]

LAGE3 Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 2, X-linked

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006014.5. 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
	LAGE3	NM_006014.5	MANE Select	c.302G>A	p.Gly101Asp	missense	Exon 2 of 3	NP_006005.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAGE3	ENST00000357360.5	TSL:1 MANE Select	c.302G>A	p.Gly101Asp	missense	Exon 2 of 3	ENSP00000349923.4	Q14657

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112086 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.0000377

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097305 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362919

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00 AC: 0 AN: 54088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3730

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841891

Other (OTH) AF: 0.0000217 AC: 1 AN: 46031

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112086 Hom.: 0 Cov.: 23 AF XY: 0.0000584 AC XY: 2 AN XY: 34246

African (AFR) AF: 0.00 AC: 0 AN: 30831

American (AMR) AF: 0.00 AC: 0 AN: 10699

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6139

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53075

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.84
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.71		Loss of MoRF binding (P = 0.0345)
MVP		0.84
MPC		0.56
ClinPred		0.85	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.82
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1037257365; hg19: chrX-153706637;