rs201474883

chrX-153870866-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_001278116.2(L1CAM):c.618C>A(p.Asp206Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,209,123 control chromosomes in the GnomAD database, including 1 homozygotes. There are 89 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00027 (1 hom. 88 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.49

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001278116.2
• BP6: Variant X-153870866-G-T is Benign according to our data. Variant chrX-153870866-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211342.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.618C>A	p.Asp206Glu	missense_variant	7/29	ENST00000370060.7
L1CAM	NM_000425.5	c.618C>A	p.Asp206Glu	missense_variant	6/28
L1CAM	NM_024003.3	c.618C>A	p.Asp206Glu	missense_variant	6/27
L1CAM	NM_001143963.2	c.603C>A	p.Asp201Glu	missense_variant	5/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.618C>A	p.Asp206Glu	missense_variant	7/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.618C>A	p.Asp206Glu	missense_variant	6/27	1		P4
L1CAM	ENST00000361981.7	c.603C>A	p.Asp201Glu	missense_variant	5/26	1		A1
L1CAM	ENST00000370055.5	c.603C>A	p.Asp201Glu	missense_variant	6/27	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000628 AC: 7 AN: 111515 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33673

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000763 AC: 14 AN: 183477 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67925

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000266 AC: 292 AN: 1097608 Hom.: 1 Cov.: 33 AF XY: 0.000242 AC XY: 88 AN XY: 362972

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

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: 0.000337

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000628 AC: 7 AN: 111515 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33673

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: 0.000132

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 09, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2016

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0, 0.98	.;D;.;D
Vest4		0.53
MutPred		0.70		.;Gain of catalytic residue at D206 (P = 0.045);.;Gain of catalytic residue at D206 (P = 0.045);
MVP		0.91
MPC		1.4
ClinPred		0.54	D
GERP RS		2.6
Varity_R		0.73
gMVP		0.96

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

Other links and lift over

dbSNP: rs201474883; hg19: chrX-153136321;