X-153864014-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001278116.2(L1CAM):c.3326G>A(p.Arg1109His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,097,584 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1109R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.000018 ( 0 hom. 9 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.228

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056392938).

BP6

Variant X-153864014-C-T is Benign according to our data. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124. Variant chrX-153864014-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 586124.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000182 (20/1097584) while in subpopulation SAS AF = 0.000222 (12/54053). AF 95% confidence interval is 0.000128. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.3326G>A	p.Arg1109His	missense_variant	Exon 26 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.3326G>A	p.Arg1109His	missense_variant	Exon 25 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.3326G>A	p.Arg1109His	missense_variant	Exon 25 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.3311G>A	p.Arg1104His	missense_variant	Exon 24 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.3326G>A	p.Arg1109His	missense_variant	Exon 26 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000222

AC:

AN:

180341

AF XY:

0.0000457

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097584

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363006

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26379

American (AMR)

AF:

0.0000284

AC:

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.000133

AC:

AN:

30185

South Asian (SAS)

AF:

0.000222

AC:

AN:

54053

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40421

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4092

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841857

Other (OTH)

AF:

0.00

AC:

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 09, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jul 18, 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

0.17

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.8

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.34

.;T;.;.

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.85

D;D;.;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.056

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;.;N

PhyloP100

0.23

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.33

N;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.53

T;T;T;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0010, 0.0060

.;B;.;B

Vest4

0.034

MutPred

0.41

.;Loss of methylation at R1109 (P = 0.0188);.;Loss of methylation at R1109 (P = 0.0188);

MVP

0.28

MPC

0.67

ClinPred

0.026

GERP RS

1.0

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.029

gMVP

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over