X-153862674-C-T

Variant names:

• chrX-153862674-C-T
• rs372990965
• NM_001278116.2:c.3763G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001278116.2(L1CAM):​c.3763G>A​(p.Ala1255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,207,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1255V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.000076 (0 hom. 39 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.364
• Publications: 0 publications found

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]

L1CAM Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011922121).
• BP6: Variant X-153862674-C-T is Benign according to our data. Variant chrX-153862674-C-T is described in ClinVar as [Benign]. Clinvar id is 2995235.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000355 (4/112832) while in subpopulation SAS AF = 0.000714 (2/2800). AF 95% confidence interval is 0.000126. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3763G>A	p.Ala1255Thr	missense_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3763G>A	p.Ala1255Thr	missense_variant	Exon 28 of 28		NP_000416.1
L1CAM	NM_024003.3	c.3751G>A	p.Ala1251Thr	missense_variant	Exon 27 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.3736G>A	p.Ala1246Thr	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.3763G>A	p.Ala1255Thr	missense_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112832 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000714

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000211 AC: 38 AN: 180095 AF XY: 0.000261

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000758 AC: 83 AN: 1094919 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 39 AN XY: 360517

African (AFR) AF: 0.0000380 AC: 1 AN: 26347

American (AMR) AF: 0.0000285 AC: 1 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19258

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00137 AC: 74 AN: 53866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839587

Other (OTH) AF: 0.000152 AC: 7 AN: 45952

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112832 Hom.: 0 Cov.: 24 AF XY: 0.000114 AC XY: 4 AN XY: 34990

African (AFR) AF: 0.0000643 AC: 2 AN: 31096

American (AMR) AF: 0.00 AC: 0 AN: 10761

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.000714 AC: 2 AN: 2800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53226

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Benign:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

L1CAM-related disorder Benign:1

Oct 10, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.9
DANN	Benign	0.64
DEOGEN2	Benign	0.32	.;T;.;T;.
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.80	T;T;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.28	.;N;.;.;.
PhyloP100		-0.36
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.32	N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.52	T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;.;.;B
Vest4		0.015
MVP		0.43
MPC		0.52
ClinPred		0.0069	T
GERP RS		-1.9
Varity_R		0.041
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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: rs372990965; hg19: chrX-153128129;