rs782756293

Positions:

• chrX-153869568-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_001278116.2(L1CAM):​c.1219C>T​(p.Arg407Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,096,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.506

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 Likely_benign. Variant got -3 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
• BP6: Variant X-153869568-G-A is Benign according to our data. Variant chrX-153869568-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568459.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1219C>T	p.Arg407Cys	missense_variant	11/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1219C>T	p.Arg407Cys	missense_variant	10/28		NP_000416.1
L1CAM	NM_024003.3	c.1219C>T	p.Arg407Cys	missense_variant	10/27		NP_076493.1
L1CAM	NM_001143963.2	c.1204C>T	p.Arg402Cys	missense_variant	9/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1219C>T	p.Arg407Cys	missense_variant	11/29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.1219C>T	p.Arg407Cys	missense_variant	10/27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.1204C>T	p.Arg402Cys	missense_variant	9/26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.1204C>T	p.Arg402Cys	missense_variant	10/27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000224 AC: 4 AN: 178588 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096695 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 2 AN XY: 362357

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25641508) -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2023

- -

L1CAM-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	.;D;.;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.5	.;M;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.39
MutPred		0.64		.;Loss of disorder (P = 0.0986);.;Loss of disorder (P = 0.0986);
MVP		0.76
MPC		1.7
ClinPred		0.48	T
GERP RS		4.5
Varity_R		0.48
gMVP		0.94

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: rs782756293; hg19: chrX-153135023; COSMIC: COSV62830614; COSMIC: COSV62830614;