rs879253716
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001278116.2(L1CAM):c.1939+5G>C variant causes a splice donor 5th base, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
L1CAM
NM_001278116.2 splice_donor_5th_base, intron
NM_001278116.2 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 1.06
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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-153867795-C-G is Pathogenic according to our data. Variant chrX-153867795-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372593.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.1939+5G>C | splice_donor_5th_base_variant, intron_variant | ENST00000370060.7 | |||
L1CAM | NM_000425.5 | c.1939+5G>C | splice_donor_5th_base_variant, intron_variant | ||||
L1CAM | NM_001143963.2 | c.1924+5G>C | splice_donor_5th_base_variant, intron_variant | ||||
L1CAM | NM_024003.3 | c.1939+5G>C | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.1939+5G>C | splice_donor_5th_base_variant, intron_variant | 5 | NM_001278116.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2016 | The c.1939+5 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 was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is predicted to destroy the natural splice donor site and cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, based on the available evidence, this variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at