rs782097679

Positions:

chrX-153865350-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_001278116.2(L1CAM):c.2698G>A(p.Gly900Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,730 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.92

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 -5 ACMG points.

BP6

Variant X-153865350-C-T is Benign according to our data. Variant chrX-153865350-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447678.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
L1CAM	NM_001278116.2 linkuse as main transcript	c.2698G>A	p.Gly900Arg	missense_variant	21/29	ENST00000370060.7
L1CAM	NM_000425.5 linkuse as main transcript	c.2698G>A	p.Gly900Arg	missense_variant	20/28
L1CAM	NM_024003.3 linkuse as main transcript	c.2698G>A	p.Gly900Arg	missense_variant	20/27
L1CAM	NM_001143963.2 linkuse as main transcript	c.2683G>A	p.Gly895Arg	missense_variant	19/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.2698G>A	p.Gly900Arg	missense_variant	21/29	5	NM_001278116.2	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33944

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00000548

AC:

AN:

182432

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67038

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

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:

0.00000547

AC:

AN:

1097730

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000356

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33944

Gnomad4 AFR

AF:

0.00

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 14, 2016

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D;.;.

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.6

.;L;.;L

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.6

D;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.93, 0.66

.;P;.;P

Vest4

0.35

MutPred

0.66

.;Loss of methylation at R901 (P = 0.0406);.;Loss of methylation at R901 (P = 0.0406);

MVP

0.74

MPC

1.6

ClinPred

0.97

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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