X-153862682-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001278116.2(L1CAM):c.3755C>A(p.Pro1252His) variant causes a missense change. 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 24)
Consequence
L1CAM
NM_001278116.2 missense
NM_001278116.2 missense
Scores
2
9
6
Clinical Significance
Conservation
PhyloP100: 5.49
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4219868).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.3755C>A | p.Pro1252His | missense_variant | 29/29 | ENST00000370060.7 | NP_001265045.1 | |
L1CAM | NM_000425.5 | c.3755C>A | p.Pro1252His | missense_variant | 28/28 | NP_000416.1 | ||
L1CAM | NM_024003.3 | c.3743C>A | p.Pro1248His | missense_variant | 27/27 | NP_076493.1 | ||
L1CAM | NM_001143963.2 | c.3728C>A | p.Pro1243His | missense_variant | 26/26 | NP_001137435.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.3755C>A | p.Pro1252His | missense_variant | 29/29 | 5 | NM_001278116.2 | ENSP00000359077.1 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MASA syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with partial agenesis of corpus callosum (MIM#304100), CRASH syndrome (MIM#303350), Hydrocephalus due to aqueductal stenosis (MIM#307000), Hydrocephalus with congenital idiopathic intestinal pseudoobstruction (MIM#307000), Hydrocephalus with Hirschsprung disease (MIM#307000), MASA syndrome (MIM#303350). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. This gene is well known for its intra- and interfamilial variability in individuals with the same variant (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to histidine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to a serine has been reported once as VUS (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.;T;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;N;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
0.056, 1.0
.;B;.;.;D
Vest4
MutPred
0.32
.;Loss of phosphorylation at S1248 (P = 0.1387);.;.;.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.