X-153862664-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278116.2(L1CAM):c.3773A>T(p.Ter1258LeuextTer264) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. *1258*) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

Genes affected

L1CAM (HGNC:6470): (L1 cell adhesion molecule) The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.3773A>T	p.Ter1258LeuextTer264	stop_lost	29/29	ENST00000370060.7
L1CAM	NM_000425.5	c.3773A>T	p.Ter1258LeuextTer264	stop_lost	28/28
L1CAM	NM_024003.3	c.3761A>T	p.Ter1254LeuextTer264	stop_lost	27/27
L1CAM	NM_001143963.2	c.3746A>T	p.Ter1249LeuextTer264	stop_lost	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.3773A>T	p.Ter1258LeuextTer264	stop_lost	29/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change disrupts the translational stop signal of the L1CAM mRNA. It is expected to extend the length of the L1CAM protein by 264 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with clinical features of L1CAM-related conditions (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	16
Dann	Benign	0.79
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
Vest4		0.25
GERP RS		4.7

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-153128119;