chrX-153869600-G-A

Variant names:

• chrX-153869600-G-A
• NM_001278116.2:c.1187C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001278116.2(L1CAM):​c.1187C>T​(p.Pro396Leu) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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.

• PM1: In a domain Ig-like C2-type 4 (size 87) in uniprot entity L1CAM_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17204079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1187C>T	p.Pro396Leu	missense_variant	Exon 11 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 28		NP_000416.1
L1CAM	NM_024003.3	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.1172C>T	p.Pro391Leu	missense_variant	Exon 9 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1187C>T	p.Pro396Leu	missense_variant	Exon 11 of 29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.1172C>T	p.Pro391Leu	missense_variant	Exon 9 of 26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.1172C>T	p.Pro391Leu	missense_variant	Exon 10 of 27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

L1CAM-related disorder Uncertain:1

Sep 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L1CAM c.1187C>T variant is predicted to result in the amino acid substitution p.Pro396Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;.;.
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.14	.;N;.;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.47	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.018	.;B;.;B
Vest4		0.25
MutPred		0.51		.;Loss of disorder (P = 0.0682);.;Loss of disorder (P = 0.0682);
MVP		0.70
MPC		1.3
ClinPred		0.39	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.93

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-153135055;