rs140678848

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001278116.2(L1CAM):c.36C>A(p.Leu12Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,208,963 control chromosomes in the GnomAD database, including 3 homozygotes. There are 778 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., 52 hem., cov: 23)

Exomes 𝑓: 0.0021 ( 2 hom. 726 hem. )

Consequence

L1CAM
NM_001278116.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0160

Publications

1 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:

ENSG00000284987 (HGNC:):

ENSG00000284987 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-153875801-G-T is Benign according to our data. Variant chrX-153875801-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.016 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00173 (194/111837) while in subpopulation NFE AF = 0.00251 (133/52965). AF 95% confidence interval is 0.00216. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 52 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
L1CAM	NM_001278116.2 link	c.36C>A	p.Leu12Leu	synonymous_variant	Exon 2 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5 link	c.36C>A	p.Leu12Leu	synonymous_variant	Exon 1 of 28		NP_000416.1
L1CAM	NM_024003.3 link	c.36C>A	p.Leu12Leu	synonymous_variant	Exon 1 of 27		NP_076493.1
L1CAM	NM_001143963.2 link	c.36C>A	p.Leu12Leu	synonymous_variant	Exon 1 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
L1CAM	ENST00000370060.7 link	c.36C>A	p.Leu12Leu	synonymous_variant	Exon 2 of 29	5	NM_001278116.2	ENSP00000359077.1
ENSG00000284987	ENST00000646191.1 link	n.*78C>A		non_coding_transcript_exon_variant	Exon 2 of 5			ENSP00000493873.1
ENSG00000284987	ENST00000646191.1 link	n.*78C>A		3_prime_UTR_variant	Exon 2 of 5			ENSP00000493873.1

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

194

AN:

111785

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00701

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.000663

GnomAD2 exomes

AF:

0.00192

AC:

349

AN:

181519

AF XY:

0.00180

show subpopulations

Gnomad AFR exome

AF:

0.000382

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.000268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00857

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.00267

GnomAD4 exome

AF:

0.00208

AC:

2287

AN:

1097126

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

726

AN XY:

362682

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

26386

American (AMR)

AF:

0.0000852

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.000206

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54123

European-Finnish (FIN)

AF:

0.00805

AC:

322

AN:

40017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3876

European-Non Finnish (NFE)

AF:

0.00222

AC:

1873

AN:

841905

Other (OTH)

AF:

0.00174

AC:

AN:

46030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

177

266

354

443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00173

AC:

194

AN:

111837

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

AN XY:

34003

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

30766

American (AMR)

AF:

0.000187

AC:

AN:

10688

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00701

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00251

AC:

133

AN:

52965

Other (OTH)

AF:

0.000655

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00218

Hom.:

Bravo

AF:

0.00122

EpiCase

AF:

0.00164

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 12, 2016

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

Oct 02, 2017

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

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.5

(source)

DANN

Benign

0.91

PhyloP100

0.016

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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