chrX-153865088-G-C

Position:

chrX-153865088-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001278116.2(L1CAM):c.2872C>G(p.Leu958Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,209,807 control chromosomes in the GnomAD database, including 31 homozygotes. There are 636 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 15 hom., 332 hem., cov: 23)

Exomes 𝑓: 0.0010 ( 16 hom. 304 hem. )

Consequence

L1CAM
NM_001278116.2 missense, splice_region

Scores

Splicing: ADA: 0.00003188

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.58

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:

L1CAM (HGNC:):

L1CAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017657876).

BP6

Variant X-153865088-G-C is Benign according to our data. Variant chrX-153865088-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 92928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1134/113001) while in subpopulation AFR AF= 0.0349 (1090/31208). AF 95% confidence interval is 0.0332. There are 15 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2 linkuse as main transcript	c.2872C>G	p.Leu958Val	missense_variant, splice_region_variant	22/29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 linkuse as main transcript	c.2872C>G	p.Leu958Val	missense_variant, splice_region_variant	21/28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 linkuse as main transcript	c.2872C>G	p.Leu958Val	missense_variant, splice_region_variant	21/27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 linkuse as main transcript	c.2857C>G	p.Leu953Val	missense_variant, splice_region_variant	20/26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.2872C>G	p.Leu958Val	missense_variant, splice_region_variant	22/29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1131

AN:

112947

Hom.:

Cov.:

AF XY:

0.00946

AC XY:

332

AN XY:

35099

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00297

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:

0.0000188

Gnomad OTH

AF:

0.00720

GnomAD3 exomes

AF:

0.00261

AC:

466

AN:

178603

Hom.:

AF XY:

0.00197

AC XY:

128

AN XY:

64881

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.000989

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.000450

GnomAD4 exome

AF:

0.00100

AC:

1097

AN:

1096806

Hom.:

Cov.:

AF XY:

0.000838

AC XY:

304

AN XY:

362640

show subpopulations

Gnomad4 AFR exome

AF:

0.0353

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.0100

AC:

1134

AN:

113001

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

332

AN XY:

35163

show subpopulations

Gnomad4 AFR

AF:

0.0349

Gnomad4 AMR

AF:

0.00296

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.000736

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.0308

AC:

118

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00280

AC:

339

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2013	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

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. -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0010

DANN

Benign

0.52

DEOGEN2

Benign

0.29

.;T;.;.

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.79

T;T;.;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.30

.;N;.;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.93

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.55

T;T;T;T

Polyphen

0.0030, 0.0

.;B;.;B

Vest4

0.060

MVP

0.39

MPC

0.55

ClinPred

0.0030

GERP RS

-9.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.13

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

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