X-153870893-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001278116.2(L1CAM):c.591T>C(p.Asn197Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,208,946 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000034 ( 0 hom. 19 hem. )

Consequence

L1CAM
NM_001278116.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.34

Publications

0 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant X-153870893-A-G is Benign according to our data. Variant chrX-153870893-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198080.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=-1.34 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000337 (37/1098015) while in subpopulation MID AF = 0.000967 (4/4136). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.591T>C	p.Asn197Asn	synonymous_variant	Exon 7 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.591T>C	p.Asn197Asn	synonymous_variant	Exon 6 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.591T>C	p.Asn197Asn	synonymous_variant	Exon 6 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.576T>C	p.Asn192Asn	synonymous_variant	Exon 5 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.591T>C	p.Asn197Asn	synonymous_variant	Exon 7 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110931

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000379

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183452

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1098015

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363373

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.000967

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

841944

Other (OTH)

AF:

0.0000651

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110931

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33153

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30425

American (AMR)

AF:

0.00

AC:

AN:

10501

Ashkenazi Jewish (ASJ)

AF:

0.000379

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2613

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52867

Other (OTH)

AF:

0.00

AC:

AN:

1491

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

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000529

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 05, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Dec 26, 2023

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.20

(source)

DANN

Benign

0.48

PhyloP100

-1.3

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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X-153870893-A-G

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