X-153862727-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001278116.2(L1CAM):c.3710C>T(p.Ala1237Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,210,824 control chromosomes in the GnomAD database, including 1 homozygotes. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1237A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000030 ( 1 hom. 10 hem. )

Consequence

L1CAM
NM_001278116.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.736

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025690228).

BP6

Variant X-153862727-G-A is Benign according to our data. Variant chrX-153862727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1050405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
L1CAM	NM_001278116.2 linkuse as main transcript	c.3710C>T	p.Ala1237Val	missense_variant	29/29	ENST00000370060.7
L1CAM	NM_000425.5 linkuse as main transcript	c.3710C>T	p.Ala1237Val	missense_variant	28/28
L1CAM	NM_024003.3 linkuse as main transcript	c.3698C>T	p.Ala1233Val	missense_variant	27/27
L1CAM	NM_001143963.2 linkuse as main transcript	c.3683C>T	p.Ala1228Val	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.3710C>T	p.Ala1237Val	missense_variant	29/29	5	NM_001278116.2	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.0000709

AC:

AN:

112889

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35045

show subpopulations

Gnomad AFR

AF:

0.0000321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000770

AC:

AN:

181770

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

67208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1097935

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

363323

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000877

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000709

AC:

AN:

112889

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35045

show subpopulations

Gnomad4 AFR

AF:

0.0000321

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00188

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	L1CAM: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The L1CAM p.Ala1233Val variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs370546591) and in control databases in 15 of 203715 chromosomes (1 homozygous; 5 hemizygous) at a frequency of 0.00007363 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 8 of 7656 chromosomes (freq: 0.001045), South Asian in 2 of 19073 chromosomes (freq: 0.000105), African in 1 of 19098 chromosomes (freq: 0.000052) and European (non-Finnish) in 4 of 91041 chromosomes (freq: 0.000044), but was not observed in the Latino, East Asian, European (Finnish), or Other populations. The p.Ala1233 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.95

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.81

T;T;.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.026

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.0040, 0.0

.;B;.;.;B

Vest4

0.10

MVP

0.71

MPC

0.55

ClinPred

0.038

GERP RS

3.0

Varity_R

0.055

gMVP

0.60

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