rs149737236

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001278116.2(L1CAM):c.2537G>T(p.Arg846Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,199,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R846H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.00017 ( 0 hom. 69 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.06

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

L1 syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
MASA syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
X-linked complicated corpus callosum dysgenesis
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
X-linked complicated spastic paraplegia type 1
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

L1CAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40040374).

BP6

Variant X-153865714-C-A is Benign according to our data. Variant chrX-153865714-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158794.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000134 (15/112314) while in subpopulation NFE AF = 0.000263 (14/53197). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.2537G>T	p.Arg846Leu	missense_variant	Exon 20 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.2537G>T	p.Arg846Leu	missense_variant	Exon 19 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.2537G>T	p.Arg846Leu	missense_variant	Exon 19 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.2522G>T	p.Arg841Leu	missense_variant	Exon 18 of 26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 link	c.2537G>T	p.Arg846Leu	missense_variant	Exon 20 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

112314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000263

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000109

AC:

AN:

183447

AF XY:

0.0000736

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 FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000169

AC:

184

AN:

1087502

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

AN XY:

353654

show subpopulations

African (AFR)

AF:

0.0000763

AC:

AN:

26197

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19317

East Asian (EAS)

AF:

0.00

AC:

AN:

30173

South Asian (SAS)

AF:

0.00

AC:

AN:

53879

European-Finnish (FIN)

AF:

0.0000988

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.000209

AC:

174

AN:

832364

Other (OTH)

AF:

0.0000874

AC:

AN:

45775

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000134

AC:

AN:

112314

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34474

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30892

American (AMR)

AF:

0.00

AC:

AN:

10712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.00

AC:

AN:

2735

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6141

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000263

AC:

AN:

53197

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hydrocephalus due to aqueductal stenosis

Uncertain:1

Jan 05, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the L1CAM gene demonstrated a sequence change, c.2537G>T, in exon 19 that results in an amino acid change, p.Arg846Leu. This sequence change does not appear to have been previously described in patients with L1CAM-related disorders and has been described in the EXAC database with a low population frequency of 0.009% (dbSNP rs149737236). The p.Arg846Leu change affects a highly conserved amino acid residue located in a domain of the L1CAM protein that is known to be functional. The p.Arg846Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg846Leu change remains unknown at this time. -

Spastic paraplegia

Benign:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 02, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Inborn genetic diseases

Benign:1

May 25, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.;.

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.80

T;T;.;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;.;L

PhyloP100

1.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.4

N;N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.013, 0.0040

.;B;.;B

Vest4

0.44

MVP

0.84

MPC

1.6

ClinPred

0.17

GERP RS

3.6

Varity_R

0.20

gMVP

0.77

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over