rs1484399991

Positions:

chrX-153864588-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001278116.2(L1CAM):c.3163G>A(p.Gly1055Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000091 in 1,209,307 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000091 ( 0 hom. 6 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.199

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20052436).

BP6

Variant X-153864588-C-T is Benign according to our data. Variant chrX-153864588-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438595.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
L1CAM	NM_001278116.2 linkuse as main transcript	c.3163G>A	p.Gly1055Arg	missense_variant	24/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5 linkuse as main transcript	c.3163G>A	p.Gly1055Arg	missense_variant	23/28		NP_000416.1
L1CAM	NM_024003.3 linkuse as main transcript	c.3163G>A	p.Gly1055Arg	missense_variant	23/27		NP_076493.1
L1CAM	NM_001143963.2 linkuse as main transcript	c.3148G>A	p.Gly1050Arg	missense_variant	22/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.3163G>A	p.Gly1055Arg	missense_variant	24/29	5	NM_001278116.2	ENSP00000359077	A1	P32004-1
L1CAM	ENST00000361699.8 linkuse as main transcript	c.3163G>A	p.Gly1055Arg	missense_variant	23/27	1		ENSP00000355380	P4	P32004-2
L1CAM	ENST00000361981.7 linkuse as main transcript	c.3148G>A	p.Gly1050Arg	missense_variant	22/26	1		ENSP00000354712	A1	P32004-3
L1CAM	ENST00000370055.5 linkuse as main transcript	c.3148G>A	p.Gly1050Arg	missense_variant	23/27	5		ENSP00000359072	A1	P32004-3

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33696

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183317

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67789

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1097791

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363165

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33696

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked complicated corpus callosum dysgenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.43

.;T;.;.

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.80

T;T;.;T

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.34

.;N;.;N

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.72

N;N;N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.0010, 0.34

.;B;.;B

Vest4

0.15

MutPred

0.42

.;Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);

MVP

0.81

MPC

0.64

ClinPred

0.024

GERP RS

1.6

Varity_R

0.096

gMVP

0.73

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

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