rs137852523

Positions:

• chrX-153870948-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001278116.2(L1CAM):​c.536T>G​(p.Ile179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 51) in uniprot entity L1CAM_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant X-153870948-A-C is Pathogenic according to our data. Variant chrX-153870948-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 9994.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.536T>G	p.Ile179Ser	missense_variant	7/29	ENST00000370060.7
L1CAM	NM_000425.5	c.536T>G	p.Ile179Ser	missense_variant	6/28
L1CAM	NM_024003.3	c.536T>G	p.Ile179Ser	missense_variant	6/27
L1CAM	NM_001143963.2	c.521T>G	p.Ile174Ser	missense_variant	5/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.536T>G	p.Ile179Ser	missense_variant	7/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.536T>G	p.Ile179Ser	missense_variant	6/27	1		P4
L1CAM	ENST00000361981.7	c.521T>G	p.Ile174Ser	missense_variant	5/26	1		A1
L1CAM	ENST00000370055.5	c.521T>G	p.Ile174Ser	missense_variant	6/27	5		A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

MASA syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	2.9	.;M;.;M
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.97, 0.18	.;D;.;B
Vest4		0.76
MutPred		0.85		.;Gain of disorder (P = 0.005);.;Gain of disorder (P = 0.005);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137852523; hg19: chrX-153136403;