rs112841948

chrX-153868962-G-AchrX-153868962-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278116.2(L1CAM):c.1268-10C>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 0.00704 in 1,178,979 control chromosomes in the GnomAD database, including 405 homozygotes. There are 2,187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (200 hom., 1090 hem., cov: 24)
  • Exomes 𝑓: 0.0040 (205 hom. 1097 hem.)
• Consequence: L1CAM NM_001278116.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001525
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.344

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=-0.79).
• BP6: Variant X-153868962-G-A is Benign according to our data. Variant chrX-153868962-G-A is described in ClinVar as [Benign]. Clinvar id is 92918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153868962-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.1268-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370060.7
L1CAM	NM_000425.5	c.1268-10C>T		splice_polypyrimidine_tract_variant, intron_variant
L1CAM	NM_001143963.2	c.1253-10C>T		splice_polypyrimidine_tract_variant, intron_variant
L1CAM	NM_024003.3	c.1268-10C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.1268-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 4004 AN: 112252 Hom.: 200 Cov.: 24 AF XY: 0.0314 AC XY: 1082 AN XY: 34408

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.0286

GnomAD3 exomes AF: 0.00968 AC: 1768 AN: 182676 Hom.: 83 AF XY: 0.00604 AC XY: 407 AN XY: 67356

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00427

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00466

GnomAD4 exome AF: 0.00402 AC: 4288 AN: 1066673 Hom.: 205 Cov.: 28 AF XY: 0.00328 AC XY: 1097 AN XY: 334823

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.000209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000996

Gnomad4 OTH exome AF: 0.00859

GnomAD4 genome AF: 0.0357 AC: 4010 AN: 112306 Hom.: 200 Cov.: 24 AF XY: 0.0316 AC XY: 1090 AN XY: 34472

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.0282

Alfa AF: 0.0190 Hom.: 53

Bravo AF: 0.0411

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2020	- -
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	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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	-0.79
Cadd	Benign	5.9
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.060		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: rs112841948; hg19: chrX-153134417;