rs1557092782
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001278116.2(L1CAM):c.704T>C(p.Met235Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M235V) has been classified as Benign.
Frequency
Genomes: not found (cov: 23)
Consequence
L1CAM
NM_001278116.2 missense
NM_001278116.2 missense
Scores
7
8
Clinical Significance
Conservation
PhyloP100: 5.14
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;
BP6
?
Variant X-153870490-A-G is Benign according to our data. Variant chrX-153870490-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432023.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.704T>C | p.Met235Thr | missense_variant | 8/29 | ENST00000370060.7 | |
L1CAM | NM_000425.5 | c.704T>C | p.Met235Thr | missense_variant | 7/28 | ||
L1CAM | NM_024003.3 | c.704T>C | p.Met235Thr | missense_variant | 7/27 | ||
L1CAM | NM_001143963.2 | c.689T>C | p.Met230Thr | missense_variant | 6/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
L1CAM | ENST00000370060.7 | c.704T>C | p.Met235Thr | missense_variant | 8/29 | 5 | NM_001278116.2 | A1 | |
L1CAM | ENST00000361699.8 | c.704T>C | p.Met235Thr | missense_variant | 7/27 | 1 | P4 | ||
L1CAM | ENST00000361981.7 | c.689T>C | p.Met230Thr | missense_variant | 6/26 | 1 | A1 | ||
L1CAM | ENST00000370055.5 | c.689T>C | p.Met230Thr | missense_variant | 7/27 | 5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
X-linked hydrocephalus syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Mar 06, 2018 | This variant was identified in a 12 year old male with mild intellectual disability, motor speech disorder, adaptive deficits, dyspraxia, hypotonia, ADHD, bifid uvula, mild dolichocephaly, large ears, mild pectus excavatum, hypoplastic nipples, and slightly tapered fingers. This variant is absent from the gnomAD database. Computational prediction models are inconsistent. This variant has not been reported previously in the literature, to our knowledge. This variant was also present in the proband's healthy, adult brother, making it unlikely to be an explanation for the proband's history. Additionally, whole exome sequencing also identified two additional variants of uncertain significance. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
D;D;D;D
Sift4G
Uncertain
T;T;T;T
Polyphen
0.31, 0.58
.;B;.;P
Vest4
MutPred
0.39
.;Gain of disorder (P = 0.0627);.;Gain of disorder (P = 0.0627);
MVP
MPC
1.2
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