X-153862663-C-G

Position:

• chrX-153862663-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001278116.2(L1CAM):​c.3774G>C​(p.Ter1258Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.606

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001278116.2 Downstream stopcodon found after 0 codons.
• PP5: Variant X-153862663-C-G is Pathogenic according to our data. Variant chrX-153862663-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449970.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3774G>C	p.Ter1258Tyrext*?	stop_lost	29/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3774G>C	p.Ter1258Tyrext*?	stop_lost	28/28		NP_000416.1
L1CAM	NM_024003.3	c.3762G>C	p.Ter1254Tyrext*?	stop_lost	27/27		NP_076493.1
L1CAM	NM_001143963.2	c.3747G>C	p.Ter1249Tyrext*?	stop_lost	26/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3774G>C	p.Ter1258Tyrext*?	stop_lost	29/29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2017

The c.3774 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.3774 G>C missense variant alters the stop codon at position 1258, changing it to a Tyrosine and extending the protein's C-terminus, with a new stop codon at position 264, denoted p.X1258TyrextX264. This variant is predicted to cause protein extension by adding 264 incorrect amino acids. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.84
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.25
GERP RS		3.9

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: rs782235888; hg19: chrX-153128118;