rs886039410
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001278116.2(L1CAM):c.2544C>A(p.Tyr848*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
L1CAM
NM_001278116.2 stop_gained
NM_001278116.2 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 2.57
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-153865707-G-T is Pathogenic according to our data. Variant chrX-153865707-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 265226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.2544C>A | p.Tyr848* | stop_gained | 20/29 | ENST00000370060.7 | NP_001265045.1 | |
L1CAM | NM_000425.5 | c.2544C>A | p.Tyr848* | stop_gained | 19/28 | NP_000416.1 | ||
L1CAM | NM_024003.3 | c.2544C>A | p.Tyr848* | stop_gained | 19/27 | NP_076493.1 | ||
L1CAM | NM_001143963.2 | c.2529C>A | p.Tyr843* | stop_gained | 18/26 | NP_001137435.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.2544C>A | p.Tyr848* | stop_gained | 20/29 | 5 | NM_001278116.2 | ENSP00000359077.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1081604Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 348572
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
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0
AN:
1081604
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29
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0
AN XY:
348572
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in L1CAM are known to be pathogenic (PMID: 19846429). This variant has not been reported in the literature in individuals with L1CAM-related disease. ClinVar contains an entry for this variant (Variation ID: 265226). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr848*) in the L1CAM gene. It is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2015 | The Y848X nonsense variant in the L1CAM gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this variant has not been reported previously to our knowledge, many other nonsense variants have been reported in the Human Gene Mutation Database in association with L1CAM-related disorders (Stenson et al., 2014). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at