dbSNP rs372990965: L1CAM:p.Ala1255Ser (chrX-153862674-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001278116.2(L1CAM):c.3763G>T(p.Ala1255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,918 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.364

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047989815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2 link	c.3763G>T	p.Ala1255Ser	missense_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1	P32004-1
L1CAM	NM_000425.5 link	c.3763G>T	p.Ala1255Ser	missense_variant	Exon 28 of 28		NP_000416.1	P32004-1
L1CAM	NM_024003.3 link	c.3751G>T	p.Ala1251Ser	missense_variant	Exon 27 of 27		NP_076493.1	P32004-2
L1CAM	NM_001143963.2 link	c.3736G>T	p.Ala1246Ser	missense_variant	Exon 26 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.3763G>T	p.Ala1255Ser	missense_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1		P32004-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1094918

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.9

DANN

Benign

0.79

DEOGEN2

Benign

0.30

.;T;.;T;.

FATHMM_MKL

Benign

0.065

LIST_S2

Uncertain

0.90

D;D;.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.048

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-1.0

.;N;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.83

N;N;N;N;N

REVEL

Benign

0.078

Sift

Benign

0.24

T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.0, 0.18

.;B;.;.;B

Vest4

0.039

MutPred

0.11

.;Gain of phosphorylation at A1255 (P = 0.0489);.;.;.;

MVP

0.62

MPC

0.60

ClinPred

0.28

GERP RS

-1.9

Varity_R

0.053

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over