X-153862674-C-T

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.3763G>A(p.Ala1255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,207,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1255V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.000076 (0 hom. 39 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.364

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 (MetaRNN=0.011922121).
• BP6: Variant X-153862674-C-T is Benign according to our data. Variant chrX-153862674-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2995235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000758 (83/1094919) while in subpopulation SAS AF= 0.00137 (74/53866). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4_exome. There are 39 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.3763G>A	p.Ala1255Thr	missense_variant	29/29	ENST00000370060.7
L1CAM	NM_000425.5	c.3763G>A	p.Ala1255Thr	missense_variant	28/28
L1CAM	NM_024003.3	c.3751G>A	p.Ala1251Thr	missense_variant	27/27
L1CAM	NM_001143963.2	c.3736G>A	p.Ala1246Thr	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.3763G>A	p.Ala1255Thr	missense_variant	29/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112832 Hom.: 0 Cov.: 24 AF XY: 0.000114 AC XY: 4 AN XY: 34990

Gnomad AFR AF: 0.0000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000714

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 38 AN: 180095 Hom.: 0 AF XY: 0.000261 AC XY: 17 AN XY: 65203

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000758 AC: 83 AN: 1094919 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 39 AN XY: 360517

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112832 Hom.: 0 Cov.: 24 AF XY: 0.000114 AC XY: 4 AN XY: 34990

Gnomad4 AFR AF: 0.0000643

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000714

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

L1CAM-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.9
Dann	Benign	0.64
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.80	T;T;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.32	N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.52	T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;.;.;B
Vest4		0.015
MVP		0.43
MPC		0.52
ClinPred		0.0069	T
GERP RS		-1.9
Varity_R		0.041
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs372990965; hg19: chrX-153128129;