rs149309725

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001278116.2(L1CAM):c.256G>A(p.Val86Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000872 in 1,204,085 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 3 hem., cov: 20)

Exomes 𝑓: 0.000080 ( 0 hom. 31 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0110

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073845714).

BP6

Variant X-153872296-C-T is Benign according to our data. Variant chrX-153872296-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197140.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00016 (17/106232) while in subpopulation NFE AF = 0.000194 (10/51549). AF 95% confidence interval is 0.000105. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.256G>A	p.Val86Met	missense_variant	Exon 5 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.256G>A	p.Val86Met	missense_variant	Exon 4 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.256G>A	p.Val86Met	missense_variant	Exon 4 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.241G>A	p.Val81Met	missense_variant	Exon 3 of 26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
L1CAM	ENST00000370060.7 link	c.256G>A	p.Val86Met	missense_variant	Exon 5 of 29	5	NM_001278116.2	ENSP00000359077.1	P32004-1
ENSG00000284987	ENST00000646191.1 link	n.*298G>A		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000493873.1	A0A2R8Y4P6
ENSG00000284987	ENST00000646191.1 link	n.*298G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000493873.1	A0A2R8Y4P6

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

106232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000773

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000194

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000120

AC:

AN:

183218

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000802

AC:

AN:

1097853

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

363221

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

26396

American (AMR)

AF:

0.0000852

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.000567

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000784

AC:

AN:

841787

Other (OTH)

AF:

0.0000651

AC:

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000160

AC:

AN:

106232

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

29170

show subpopulations

African (AFR)

AF:

0.000171

AC:

AN:

29170

American (AMR)

AF:

0.00

AC:

AN:

9616

Ashkenazi Jewish (ASJ)

AF:

0.000773

AC:

AN:

2587

East Asian (EAS)

AF:

0.00

AC:

AN:

3386

South Asian (SAS)

AF:

0.00

AC:

AN:

2090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000194

AC:

AN:

51549

Other (OTH)

AF:

0.00

AC:

AN:

1359

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.564

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:

0.000205

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 05, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 23, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.50

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.31

.;T;.;.;T;T;T

FATHMM_MKL

Benign

0.039

LIST_S2

Uncertain

0.93

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.074

T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.2

.;L;.;L;.;.;.

PhyloP100

-0.011

PrimateAI

Benign

0.45

PROVEAN

Benign

0.74

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

REVEL

Benign

0.25

Sift

Benign

0.97

T;T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;.;.;D

Polyphen

0.42, 0.65

.;B;.;P;.;.;.

Vest4

0.18

MVP

0.75

MPC

1.4

ClinPred

0.035

GERP RS

3.9

Varity_R

0.094

gMVP

0.80

Mutation Taster

=100/0

polymorphism

(source)

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

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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