X-153872214-C-T

Variant names:

• chrX-153872214-C-T
• rs781908326
• NM_001278116.2:c.338G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001278116.2(L1CAM):​c.338G>A​(p.Arg113His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000456 in 1,206,417 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000046 (0 hom. 12 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.127
• Publications: 1 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

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.101777434).
• BP6: Variant X-153872214-C-T is Benign according to our data. Variant chrX-153872214-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458213.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000367 (4/109077) while in subpopulation AMR AF = 0.000297 (3/10100). AF 95% confidence interval is 0.0000803. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.338G>A	p.Arg113His	missense	Exon 5 of 29	NP_001265045.1
	L1CAM	NM_000425.5		c.338G>A	p.Arg113His	missense	Exon 4 of 28	NP_000416.1
	L1CAM	NM_024003.3		c.338G>A	p.Arg113His	missense	Exon 4 of 27	NP_076493.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.338G>A	p.Arg113His	missense	Exon 5 of 29	ENSP00000359077.1
	L1CAM	ENST00000361699.8	TSL:1	c.338G>A	p.Arg113His	missense	Exon 4 of 27	ENSP00000355380.4
	L1CAM	ENST00000361981.7	TSL:1	c.323G>A	p.Arg108His	missense	Exon 3 of 26	ENSP00000354712.3

Frequencies

GnomAD3 genomes AF: 0.0000367 AC: 4 AN: 109077 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000297

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 39 AN: 183388 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.0000465 AC: 51 AN: 1097340 Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 12 AN XY: 362718

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00108 AC: 38 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841318

Other (OTH) AF: 0.0000217 AC: 1 AN: 46064

GnomAD4 genome AF: 0.0000367 AC: 4 AN: 109077 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31441

African (AFR) AF: 0.00 AC: 0 AN: 30015

American (AMR) AF: 0.000297 AC: 3 AN: 10100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3443

South Asian (SAS) AF: 0.00 AC: 0 AN: 2298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5829

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

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52427

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.0000686 Hom.: 1

Bravo AF: 0.000215

ExAC AF: 0.000206 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

History of neurodevelopmental disorder Uncertain:1

Sep 16, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R113H variant (also known as c.338G>A), located in coding exon 4 of the L1CAM gene, results from a G to A substitution at nucleotide position 338. The arginine at codon 113 is replaced by histidine, an amino acid with highly similar properties. This variant co-segregated with disease in one family tested in our laboratory. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Spastic paraplegia Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

L1CAM-related disorder Benign:1

Apr 18, 2023

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.13
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.72		Loss of MoRF binding (P = 0.008)
MVP		0.65
MPC		1.7
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.72
gMVP		0.92
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781908326; hg19: chrX-153137669; COSMIC: COSV62827252; COSMIC: COSV62827252;