rs140240430

Variant names:

• chrX-153868136-G-A
• rs140240430
• NM_001278116.2:c.1704-14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278116.2(L1CAM):​c.1704-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,208,061 control chromosomes in the GnomAD database, including 50 homozygotes. There are 867 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.014 (34 hom., 409 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (16 hom. 458 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.903
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant X-153868136-G-A is Benign according to our data. Variant chrX-153868136-G-A is described in ClinVar as [Benign]. Clinvar id is 92919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (1548/111518) while in subpopulation AFR AF = 0.0476 (1459/30667). AF 95% confidence interval is 0.0455. There are 34 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1704-14C>T		intron_variant	Intron 14 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1704-14C>T		intron_variant	Intron 13 of 27		NP_000416.1
L1CAM	NM_024003.3	c.1704-14C>T		intron_variant	Intron 13 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.1689-14C>T		intron_variant	Intron 12 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1704-14C>T		intron_variant	Intron 14 of 28	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1543 AN: 111466 Hom.: 34 Cov.: 23

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.00808

GnomAD2 exomes AF: 0.00396 AC: 718 AN: 181159 AF XY: 0.00247

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00151 AC: 1654 AN: 1096543 Hom.: 16 Cov.: 32 AF XY: 0.00126 AC XY: 458 AN XY: 362253

African (AFR) AF: 0.0456 AC: 1204 AN: 26396

American (AMR) AF: 0.00307 AC: 108 AN: 35185

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54109

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39289

Middle Eastern (MID) AF: 0.00315 AC: 13 AN: 4132

European-Non Finnish (NFE) AF: 0.000171 AC: 144 AN: 841782

Other (OTH) AF: 0.00393 AC: 181 AN: 46069

GnomAD4 genome AF: 0.0139 AC: 1548 AN: 111518 Hom.: 34 Cov.: 23 AF XY: 0.0121 AC XY: 409 AN XY: 33710

African (AFR) AF: 0.0476 AC: 1459 AN: 30667

American (AMR) AF: 0.00588 AC: 62 AN: 10545

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6164

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.000265 AC: 14 AN: 52928

Other (OTH) AF: 0.00798 AC: 12 AN: 1504

Alfa AF: 0.00648 Hom.: 31

Bravo AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.18
DANN	Benign	0.50
PhyloP100		0.90
BranchPoint Hunter		1.0
PromoterAI		0.069	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140240430; hg19: chrX-153133591;