rs140240430

chrX-153868136-G-A

Variant summary

Our verdict is Benign. Variant got -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 splice polypyrimidine tract, 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 (★★).

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

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 Benign. Variant got -20 ACMG points.

• BP4: 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.1704-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370060.7
L1CAM	NM_000425.5	c.1704-14C>T		splice_polypyrimidine_tract_variant, intron_variant
L1CAM	NM_001143963.2	c.1689-14C>T		splice_polypyrimidine_tract_variant, intron_variant
L1CAM	NM_024003.3	c.1704-14C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.1704-14C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1543 AN: 111466 Hom.: 34 Cov.: 23 AF XY: 0.0121 AC XY: 407 AN XY: 33648

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

GnomAD3 exomes AF: 0.00396 AC: 718 AN: 181159 Hom.: 16 AF XY: 0.00247 AC XY: 163 AN XY: 65999

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 SAS exome AF: 0.000158

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

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.00393

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

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00798

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2013	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.18
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs140240430; hg19: chrX-153133591;