X-153866869-C-T

Position:

chrX-153866869-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001278116.2(L1CAM):c.2211G>A(p.Pro737=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000962 in 1,205,873 control chromosomes in the GnomAD database, including 4 homozygotes. There are 542 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P737P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., 17 hem., cov: 22)

Exomes 𝑓: 0.0010 ( 4 hom. 525 hem. )

Consequence

L1CAM
NM_001278116.2 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.87

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant X-153866869-C-T is Benign according to our data. Variant chrX-153866869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153866869-C-T is described in Lovd as [Likely_benign]. Variant chrX-153866869-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.87 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000564 (63/111775) while in subpopulation SAS AF= 0.00856 (23/2686). AF 95% confidence interval is 0.00585. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
L1CAM	NM_001278116.2 linkuse as main transcript	c.2211G>A	p.Pro737=	splice_region_variant, synonymous_variant	19/29	ENST00000370060.7
L1CAM	NM_000425.5 linkuse as main transcript	c.2211G>A	p.Pro737=	splice_region_variant, synonymous_variant	18/28
L1CAM	NM_024003.3 linkuse as main transcript	c.2211G>A	p.Pro737=	splice_region_variant, synonymous_variant	18/27
L1CAM	NM_001143963.2 linkuse as main transcript	c.2196G>A	p.Pro732=	splice_region_variant, synonymous_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7 linkuse as main transcript	c.2211G>A	p.Pro737=	splice_region_variant, synonymous_variant	19/29	5	NM_001278116.2	A1	P32004-1

Frequencies

GnomAD3 genomes

AF:

0.000573

AC:

AN:

111722

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

33902

show subpopulations

Gnomad AFR

AF:

0.0000979

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000490

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00171

AC:

306

AN:

179429

Hom.:

AF XY:

0.00256

AC XY:

167

AN XY:

65153

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.000330

Gnomad ASJ exome

AF:

0.00135

Gnomad EAS exome

AF:

0.0000727

Gnomad SAS exome

AF:

0.0104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000997

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.00100

AC:

1097

AN:

1094098

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

525

AN XY:

359766

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000370

Gnomad4 ASJ exome

AF:

0.00129

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000435

Gnomad4 OTH exome

AF:

0.00170

GnomAD4 genome

AF:

0.000564

AC:

AN:

111775

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

33965

show subpopulations

Gnomad4 AFR

AF:

0.0000977

Gnomad4 AMR

AF:

0.000283

Gnomad4 ASJ

AF:

0.00151

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00856

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000490

Gnomad4 OTH

AF:

0.00198

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.000499

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2017

This alteration is classified as 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. -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.27

DANN

Benign

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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