rs201151358

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2

The NM_001278116.2(L1CAM):c.113C>T(p.Thr38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,206,671 control chromosomes in the GnomAD database, including 1 homozygotes. There are 220 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T38T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.00060 ( 1 hom. 212 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.268756).

BP6

Variant X-153872676-G-A is Benign according to our data. Variant chrX-153872676-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153872676-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000602 (659/1095498) while in subpopulation NFE AF= 0.000756 (635/839624). AF 95% confidence interval is 0.000707. There are 1 homozygotes in gnomad4_exome. There are 212 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
L1CAM	NM_001278116.2 linkuse as main transcript	c.113C>T	p.Thr38Met	missense_variant	4/29	ENST00000370060.7
L1CAM	NM_000425.5 linkuse as main transcript	c.113C>T	p.Thr38Met	missense_variant	3/28
L1CAM	NM_024003.3 linkuse as main transcript	c.113C>T	p.Thr38Met	missense_variant	3/27
L1CAM	NM_001143963.2 linkuse as main transcript	c.98C>T	p.Thr33Met	missense_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.113C>T	p.Thr38Met	missense_variant	4/29	5	NM_001278116.2	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.000261

AC:

AN:

111173

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

33357

show subpopulations

Gnomad AFR

AF:

0.000295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000954

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000359

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000251

AC:

AN:

183381

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

67833

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000602

AC:

659

AN:

1095498

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

212

AN XY:

360902

show subpopulations

Gnomad4 AFR exome

AF:

0.000266

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000756

Gnomad4 OTH exome

AF:

0.000283

GnomAD4 genome

AF:

0.000261

AC:

AN:

111173

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

33357

show subpopulations

Gnomad4 AFR

AF:

0.000295

Gnomad4 AMR

AF:

0.0000954

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000359

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 05, 2021

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2017

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. -

X-linked hydrocephalus syndrome;C0795953:MASA syndrome;C1839909:X-linked complicated corpus callosum dysgenesis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 06, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2018

This variant is associated with the following publications: (PMID: 26891472, 19846429) -

L1CAM-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

Cadd

Uncertain

Dann

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.27

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

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0, 1.0

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

Vest4

0.55

MVP

0.78

MPC

1.5

ClinPred

0.20

GERP RS

4.7

Varity_R

0.52

gMVP

0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over