rs886039405
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001278116.2(L1CAM):c.807-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,836 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001278116.2 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.807-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000370060.7 | |||
L1CAM | NM_000425.5 | c.807-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
L1CAM | NM_001143963.2 | c.792-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
L1CAM | NM_024003.3 | c.807-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.807-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_001278116.2 | A1 | |||
L1CAM | ENST00000361699.8 | c.807-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | P4 | ||||
L1CAM | ENST00000361981.7 | c.792-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | A1 | ||||
L1CAM | ENST00000370055.5 | c.792-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095836Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 361354
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2016 | The c.807-6 G>A splice site variant in the L1CAM gene has been previously reported in association with L1CAM-related disorders (MacFarlane et al., 1997; Du et al., 1998; Adle-Biassette et al., 2013). This pathogenic variant creates a new splice acceptor site upstream of the natural splice acceptor site in intron 7, and causes abnormal gene splicing leading to a premature stop codon (MacFarlane et al., 1997). The variant 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 10, 2017 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2022 | This sequence change falls in intron 7 of the L1CAM gene. It does not directly change the encoded amino acid sequence of the L1CAM protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with X-linked L1 syndrome (PMID: 9195224, 9521424, 19953645, 23820807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265221). Studies have shown that this variant results in activation of a cryptic acceptor splice site and introduces a premature termination codon (PMID: 9195224). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
L1 syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2021 | Variant summary: L1CAM c.807-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3` acceptor site. Three predict the variant weakens a canonical 3` acceptor site. One predicts the variant abolishes a canonical 3` acceptor site. At least one publication reports experimental evidence that this variant results in causing aberrant splicing by creating a novel intron acceptor site (MacFarlane_1997, protein changed and predicted as p.Phe269LeufsX39 in L1CAM Mutation Database). The variant was absent in 182129 control chromosomes (gnomAD and publication data). c.807-6G>A has been reported in the literature in individuals affected with X-linked hydrocephalus and MASA syndrome (Du_1998, MacFarlane_1997, Nunes_2009). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at