rs782017677

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_001278116.2(L1CAM):c.3764C>T(p.Ala1255Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000746 in 1,206,987 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1255T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000064 ( 0 hom. 4 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.95

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11401284).

BP6

Variant X-153862673-G-A is Benign according to our data. Variant chrX-153862673-G-A is described in ClinVar as [Benign]. Clinvar id is 2911131.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000177 (2/112828) while in subpopulation EAS AF = 0.000559 (2/3576). AF 95% confidence interval is 0.0000984. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.3764C>T	p.Ala1255Val	missense_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.3764C>T	p.Ala1255Val	missense_variant	Exon 28 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.3752C>T	p.Ala1251Val	missense_variant	Exon 27 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.3737C>T	p.Ala1246Val	missense_variant	Exon 26 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.3764C>T	p.Ala1255Val	missense_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000559

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:

0.0000388

AC:

AN:

180201

AF XY:

0.0000613

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000433

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1094159

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

359805

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26333

American (AMR)

AF:

0.0000284

AC:

AN:

35150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19272

East Asian (EAS)

AF:

0.000166

AC:

AN:

30185

South Asian (SAS)

AF:

0.00

AC:

AN:

53888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40473

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838813

Other (OTH)

AF:

0.0000218

AC:

AN:

45930

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

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112828

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31092

American (AMR)

AF:

0.00

AC:

AN:

10768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.000559

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2803

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53235

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

.;T;.;T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D;.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.1

.;L;.;.;.

PhyloP100

6.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Benign

0.038

Sift

Uncertain

0.0080

D;D;D;T;D

Sift4G

Benign

0.093

T;T;T;D;D

Polyphen

0.0030, 0.040

.;B;.;.;B

Vest4

0.038

MutPred

0.22

.;Gain of sheet (P = 0.0477);.;.;.;

MVP

0.75

MPC

0.70

ClinPred

0.18

GERP RS

4.7

Varity_R

0.17

gMVP

0.36

Mutation Taster

=78/22

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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rs782017677

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