rs1557092050

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001278116.2(L1CAM):c.1358C>T(p.Ala453Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,208,681 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A453A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

Variant links:

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]

L1CAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
L1CAM	NM_001278116.2 linkuse as main transcript	c.1358C>T	p.Ala453Val	missense_variant	12/29	ENST00000370060.7
L1CAM	NM_000425.5 linkuse as main transcript	c.1358C>T	p.Ala453Val	missense_variant	11/28
L1CAM	NM_024003.3 linkuse as main transcript	c.1358C>T	p.Ala453Val	missense_variant	11/27
L1CAM	NM_001143963.2 linkuse as main transcript	c.1343C>T	p.Ala448Val	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.1358C>T	p.Ala453Val	missense_variant	12/29	5	NM_001278116.2	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112295

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34463

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183395

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67863

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096386

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112295

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34463

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt L1CAM protein function. ClinVar contains an entry for this variant (Variation ID: 458211). This variant has not been reported in the literature in individuals affected with L1CAM-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 453 of the L1CAM protein (p.Ala453Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

D;D;.;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-0.66

MutationTaster

Benign

0.60

N;N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Benign

0.23

Sift

Benign

0.084

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.93, 0.95

.;P;.;P

Vest4

0.13

MutPred

0.76

.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);

MVP

0.73

MPC

0.68

ClinPred

0.40

GERP RS

4.6

Varity_R

0.17

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over