rs766942777
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001330092.2(NRXN1):c.41C>T(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,295,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001330092.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.3365-109939C>T | intron_variant | ENST00000401669.7 | NP_001317007.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.3365-109939C>T | intron_variant | 5 | NM_001330078.2 | ENSP00000385017.2 |
Frequencies
GnomAD3 genomes AF: 0.000258 AC: 39AN: 150916Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000627 AC: 19AN: 30310Hom.: 0 AF XY: 0.000489 AC XY: 9AN XY: 18396
GnomAD4 exome AF: 0.000401 AC: 459AN: 1144260Hom.: 0 Cov.: 30 AF XY: 0.000398 AC XY: 221AN XY: 555956
GnomAD4 genome AF: 0.000258 AC: 39AN: 151024Hom.: 0 Cov.: 32 AF XY: 0.000285 AC XY: 21AN XY: 73774
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | NRXN1: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is in the shorter transcript of NRXN1 (NM_138735.2), and alters a residue that is predicted to be in the signal peptide of the beta-neurexin protein (Zweier et al., 2009); This variant is associated with the following publications: (PMID: 18179900, 24832020, 21424692, 22504536, 17034946, 28289584, 29221905, 18728070) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2017 | The p.S14L variant (also known as c.41C>T), located in coding exon 1 of the NRXN1 gene, results from a C to T substitution at nucleotide position 41. The serine at codon 14 is replaced by leucine, an amino acid with dissimilar properties. In four separate studies, this alteration was detected in 5/944 individuals with ASD, ID, seizures, schizophrenia, and/or non syndromic ID; however, the phenotype of these individuals was variable. In addition, this alteration has been detected in 1/1330 controls (Camacho-Garcia RJ et al. Neurobiol. Dis., 2012 Jul;47:135-43; Yangngam S et al. Genet Test Mol Biomarkers, 2014 Jul;18:510-5; Gauthier J et al. Hum. Genet., 2011 Oct;130:563-73; Feng J et al. Neurosci. Lett., 2006 Nov;409:10-3). In one functional study, authors claimed that cell surface trafficking in COS cells containing this variant was not significantly different than cells containing wild type protein; however, details regarding this data were not provided (Gauthier J et al. Hum. Genet., 2011 Oct;130:563-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pitt-Hopkins-like syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at