NM_001278116.2:c.3737C>A

Variant names:

• chrX-153862700-G-T
• rs1557089253
• NM_001278116.2:c.3737C>A

Variant summary

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

The NM_001278116.2(L1CAM):​c.3737C>A​(p.Ala1246Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,345 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3737C>A	p.Ala1246Asp	missense_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3737C>A	p.Ala1246Asp	missense_variant	Exon 28 of 28		NP_000416.1
L1CAM	NM_024003.3	c.3725C>A	p.Ala1242Asp	missense_variant	Exon 27 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.3710C>A	p.Ala1237Asp	missense_variant	Exon 26 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3737C>A	p.Ala1246Asp	missense_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000220 AC: 4 AN: 181541 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097345 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362773

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1246 of the L1CAM protein (p.Ala1246Asp). This variant is present in population databases (no rsID available, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with L1CAM-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on L1CAM protein function. 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
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;D;.;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.48, 0.095	.;P;.;.;B
Vest4		0.68
MutPred		0.13		.;Gain of catalytic residue at A1246 (P = 0.096);.;.;.;
MVP		0.99
MPC		1.7
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs1557089253; hg19: chrX-153128155;