X-154478028-G-A

Variant names:

• chrX-154478028-G-A
• rs112776954
• NM_006014.5:c.348C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_006014.5(LAGE3):​c.348C>T​(p.Leu116Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,635 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L116L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: LAGE3 NM_006014.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• 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]

PLXNA3 (HGNC:9101): (plexin A3) This gene encodes a member of the plexin class of proteins. The encoded protein is a class 3 semaphorin receptor, and may be involved in cytoskeletal remodeling and as well as apoptosis. Studies of a similar gene in zebrafish suggest that it is important for axon pathfinding in the developing nervous system. This gene may be associated with tumor progression. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 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.348C>T	p.Leu116Leu	synonymous	Exon 3 of 3	NP_006005.2
	PLXNA3	NM_017514.5	MANE Select	c.*5343G>A		downstream_gene	N/A	NP_059984.3	P51805

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAGE3	ENST00000357360.5	TSL:1 MANE Select	c.348C>T	p.Leu116Leu	synonymous	Exon 3 of 3	ENSP00000349923.4	Q14657
	PLXNA3	ENST00000369682.4	TSL:1 MANE Select	c.*5343G>A		downstream_gene	N/A	ENSP00000358696.3	P51805

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097635 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362991

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841649

Other (OTH) AF: 0.0000217 AC: 1 AN: 46073

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.79
PhyloP100		0.071

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: rs112776954; hg19: chrX-153706367;