Variant rs1369743518 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278116.2(L1CAM):c.3654G>C(p.Gln1218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.80

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
L1CAM	NM_001278116.2 linkuse as main transcript	c.3654G>C	p.Gln1218His	missense_variant	29/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5 linkuse as main transcript	c.3654G>C	p.Gln1218His	missense_variant	28/28		NP_000416.1
L1CAM	NM_024003.3 linkuse as main transcript	c.3642G>C	p.Gln1214His	missense_variant	27/27		NP_076493.1
L1CAM	NM_001143963.2 linkuse as main transcript	c.3627G>C	p.Gln1209His	missense_variant	26/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.3654G>C	p.Gln1218His	missense_variant	29/29	5	NM_001278116.2	ENSP00000359077	A1	P32004-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181701

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67381

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:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097951

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363311

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:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MASA syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 22, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.3654G>C (p.Q1218H) alteration is located in exon 28 (coding exon 28) of the L1CAM gene. This alteration results from a G to C substitution at nucleotide position 3654, causing the glutamine (Q) at amino acid position 1218 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D;.;D;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D;.;D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.4

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.044

D;T;D;D;D

Polyphen

1.0

.;D;.;.;D

Vest4

0.31

MutPred

0.19

.;Gain of catalytic residue at Q1218 (P = 0.0946);.;.;.;

MVP

0.95

MPC

1.4

ClinPred

0.91

GERP RS

4.6

Varity_R

0.80

gMVP

0.77

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