rs1042512

chrX-153870192-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001278116.2(L1CAM):c.855C>T(p.Ala285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,210,597 control chromosomes in the GnomAD database, including 265 homozygotes. There are 1,873 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (133 hom., 913 hem., cov: 24)
  • Exomes 𝑓: 0.0033 (132 hom. 960 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.20

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 -16 ACMG points.

• BP6: Variant X-153870192-G-A is Benign according to our data. Variant chrX-153870192-G-A is described in ClinVar as [Benign]. Clinvar id is 158796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153870192-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.855C>T	p.Ala285=	synonymous_variant	9/29	ENST00000370060.7
L1CAM	NM_000425.5	c.855C>T	p.Ala285=	synonymous_variant	8/28
L1CAM	NM_024003.3	c.855C>T	p.Ala285=	synonymous_variant	8/27
L1CAM	NM_001143963.2	c.840C>T	p.Ala280=	synonymous_variant	7/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.855C>T	p.Ala285=	synonymous_variant	9/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.855C>T	p.Ala285=	synonymous_variant	8/27	1		P4
L1CAM	ENST00000361981.7	c.840C>T	p.Ala280=	synonymous_variant	7/26	1		A1
L1CAM	ENST00000370055.5	c.840C>T	p.Ala280=	synonymous_variant	8/27	5		A1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 3346 AN: 112761 Hom.: 133 Cov.: 24 AF XY: 0.0260 AC XY: 906 AN XY: 34903

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.0276

GnomAD3 exomes AF: 0.00806 AC: 1474 AN: 182899 Hom.: 51 AF XY: 0.00510 AC XY: 344 AN XY: 67403

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000316

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00332 AC: 3641 AN: 1097783 Hom.: 132 Cov.: 33 AF XY: 0.00264 AC XY: 960 AN XY: 363183

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.000206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00697

GnomAD4 genome AF: 0.0297 AC: 3352 AN: 112814 Hom.: 133 Cov.: 24 AF XY: 0.0261 AC XY: 913 AN XY: 34966

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00109

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.0272

Alfa AF: 0.0151 Hom.: 77

Bravo AF: 0.0343

EpiCase AF: 0.000164

EpiControl AF: 0.000356

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	Athena Diagnostics	Feb 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2013	- -

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

Apr 01, 2020

- -

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	-0.86
Cadd	Benign	6.9
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1042512; hg19: chrX-153135647;