chrX-153868067-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_001278116.2(L1CAM):c.1759G>C(p.Gly587Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000381 in 1,208,629 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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. G587S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000031 ( 0 hom. 6 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 7.09

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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.055904865).

BP6

Variant X-153868067-C-G is Benign according to our data. Variant chrX-153868067-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435686.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000108 (12/110880) while in subpopulation EAS AF = 0.00285 (10/3509). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. 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
L1CAM	NM_001278116.2 link	c.1759G>C	p.Gly587Arg	missense_variant	Exon 15 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5 link	c.1759G>C	p.Gly587Arg	missense_variant	Exon 14 of 28		NP_000416.1
L1CAM	NM_024003.3 link	c.1759G>C	p.Gly587Arg	missense_variant	Exon 14 of 27		NP_076493.1
L1CAM	NM_001143963.2 link	c.1744G>C	p.Gly582Arg	missense_variant	Exon 13 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 link	c.1759G>C	p.Gly587Arg	missense_variant	Exon 15 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

110826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000158

AC:

AN:

183120

AF XY:

0.0000887

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1097749

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363163

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.0000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000927

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40287

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841899

Other (OTH)

AF:

0.000108

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000108

AC:

AN:

110880

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

33106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30433

American (AMR)

AF:

0.000190

AC:

AN:

10513

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00285

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52790

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 12, 2018

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. -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

.;D;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.056

T;T;T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

4.3

.;H;.;H

PhyloP100

7.1

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.44

MVP

0.98

MPC

1.6

ClinPred

0.72

GERP RS

5.7

PromoterAI

0.018

Neutral

(source)

Varity_R

0.99

gMVP

0.96

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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