chrX-153865714-C-T

Position:

chrX-153865714-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001278116.2(L1CAM):c.2537G>A(p.Arg846His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,199,872 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 0.000044 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.06

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36058566).

BP6

Variant X-153865714-C-T is Benign according to our data. Variant chrX-153865714-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 588694.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
L1CAM	NM_001278116.2 linkuse as main transcript	c.2537G>A	p.Arg846His	missense_variant	20/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5 linkuse as main transcript	c.2537G>A	p.Arg846His	missense_variant	19/28		NP_000416.1
L1CAM	NM_024003.3 linkuse as main transcript	c.2537G>A	p.Arg846His	missense_variant	19/27		NP_076493.1
L1CAM	NM_001143963.2 linkuse as main transcript	c.2522G>A	p.Arg841His	missense_variant	18/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.2537G>A	p.Arg846His	missense_variant	20/29	5	NM_001278116.2	ENSP00000359077	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.0000445

AC:

AN:

112314

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34474

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183447

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67897

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000146

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1087501

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

353653

show subpopulations

Gnomad4 AFR exome

AF:

0.000115

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000841

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000445

AC:

AN:

112371

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34541

show subpopulations

Gnomad4 AFR

AF:

0.000129

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000654

Bravo

AF:

0.0000642

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2017

The p.R846H variant (also known as c.2537G>A), located in coding exon 19 of the L1CAM gene, results from a G to A substitution at nucleotide position 2537. The arginine at codon 846 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;D;.;.

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.5

.;M;.;M

MutationTaster

Benign

0.98

N;N;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.99, 0.97

.;D;.;D

Vest4

0.34

MutPred

0.68

.;Loss of MoRF binding (P = 0.0067);.;Loss of MoRF binding (P = 0.0067);

MVP

0.65

MPC

1.6

ClinPred

0.25

GERP RS

3.6

Varity_R

0.11

gMVP

0.69

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