rs142277193

chrX-153863488-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278116.2(L1CAM):c.3519C>T(p.Phe1173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,209,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 158 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 50 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (0 hom. 108 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-153863488-G-A is Benign according to our data. Variant chrX-153863488-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 167236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00182 (203/111836) while in subpopulation EAS AF= 0.00566 (20/3536). AF 95% confidence interval is 0.0049. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 50 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.3519C>T	p.Phe1173=	synonymous_variant	27/29	ENST00000370060.7
L1CAM	NM_000425.5	c.3519C>T	p.Phe1173=	synonymous_variant	26/28
L1CAM	NM_024003.3	c.3519C>T	p.Phe1173=	synonymous_variant	26/27
L1CAM	NM_001143963.2	c.3504C>T	p.Phe1168=	synonymous_variant	25/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.3519C>T	p.Phe1173=	synonymous_variant	27/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 203 AN: 111781 Hom.: 0 Cov.: 23 AF XY: 0.00147 AC XY: 50 AN XY: 33971

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00564

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.00116 AC: 212 AN: 183136 Hom.: 1 AF XY: 0.00101 AC XY: 68 AN XY: 67652

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00715

Gnomad SAS exome AF: 0.000788

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000353 AC: 388 AN: 1097746 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 108 AN XY: 363118

Gnomad4 AFR exome AF: 0.00527

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00576

Gnomad4 SAS exome AF: 0.000573

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.000434

GnomAD4 genome AF: 0.00182 AC: 203 AN: 111836 Hom.: 0 Cov.: 23 AF XY: 0.00147 AC XY: 50 AN XY: 34036

Gnomad4 AFR AF: 0.00559

Gnomad4 AMR AF: 0.000751

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00566

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.00199

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2016

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.25
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142277193; hg19: chrX-153128943;