rs7885771

Positions:

• chrX-153866877-G-A

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.2209-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,202,981 control chromosomes in the GnomAD database, including 818 homozygotes. There are 3,256 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (410 hom., 1574 hem., cov: 22)
  • Exomes 𝑓: 0.0059 (408 hom. 1682 hem.)
• Consequence: L1CAM NM_001278116.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.04932
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.07

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=-0.73).
• BP6: Variant X-153866877-G-A is Benign according to our data. Variant chrX-153866877-G-A is described in ClinVar as [Benign]. Clinvar id is 92923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153866877-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.2209-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.2209-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_000416.1
L1CAM	NM_001143963.2	c.2194-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001137435.1
L1CAM	NM_024003.3	c.2209-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_076493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.2209-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001278116.2	ENSP00000359077	A1

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 5947 AN: 111572 Hom.: 409 Cov.: 22 AF XY: 0.0462 AC XY: 1560 AN XY: 33756

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000565

Gnomad OTH AF: 0.0428

GnomAD3 exomes AF: 0.0149 AC: 2666 AN: 179342 Hom.: 182 AF XY: 0.00933 AC XY: 607 AN XY: 65056

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.00741

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000421

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.00672

GnomAD4 exome AF: 0.00588 AC: 6418 AN: 1091356 Hom.: 408 Cov.: 31 AF XY: 0.00471 AC XY: 1682 AN XY: 357272

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.00956

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0534 AC: 5963 AN: 111625 Hom.: 410 Cov.: 22 AF XY: 0.0465 AC XY: 1574 AN XY: 33819

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000565

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0280 Hom.: 154

Bravo AF: 0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2013	- -
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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.049
dbscSNV1_RF	Benign	0.31
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

Publications

LitVar

Other links and lift over

dbSNP: rs7885771; hg19: chrX-153132332;