dbSNP rs781908326: L1CAM:p.Arg113Leu (chrX-153872214-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278116.2(L1CAM):c.338G>T(p.Arg113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.127

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:

ENSG00000284987 (HGNC:):

ENSG00000284987 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.338G>T	p.Arg113Leu	missense_variant	Exon 5 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.338G>T	p.Arg113Leu	missense_variant	Exon 4 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.338G>T	p.Arg113Leu	missense_variant	Exon 4 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.323G>T	p.Arg108Leu	missense_variant	Exon 3 of 26		NP_001137435.1	P32004-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7 link	c.338G>T	p.Arg113Leu	missense_variant	Exon 5 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1
ENSG00000284987	ENST00000646191.1 link	n.*380G>T		downstream_gene_variant				ENSP00000493873.1		A0A2R8Y4P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183388

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67838

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

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097343

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362719

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D;.;.;T;T

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

D;D;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.49

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;L;.;.

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D;.;.

Polyphen

1.0, 0.95

.;D;.;P;.;.

Vest4

0.61

MutPred

0.66

.;Loss of MoRF binding (P = 0.0083);.;Loss of MoRF binding (P = 0.0083);Loss of MoRF binding (P = 0.0083);.;

MVP

0.59

MPC

1.7

ClinPred

0.86

GERP RS

5.0

Varity_R

0.76

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over