NM_001330078.2:c.1158+26A>T
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001330078.2(NRXN1):c.1158+26A>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,554,320 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00093 ( 4 hom. )
Consequence
NRXN1
NM_001330078.2 intron
NM_001330078.2 intron
Scores
2
Splicing: ADA: 0.001757
2
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
NRXN1 (HGNC:8008): (neurexin 1) This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
Variant 2-50621200-T-A is Benign according to our data. Variant chr2-50621200-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129818.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=5}. Variant chr2-50621200-T-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000736 (112/152216) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000736 AC: 112AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00112 AC: 195AN: 173744Hom.: 0 AF XY: 0.00137 AC XY: 125AN XY: 91416
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GnomAD4 exome AF: 0.000934 AC: 1310AN: 1402104Hom.: 4 Cov.: 28 AF XY: 0.00106 AC XY: 731AN XY: 692540
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GnomAD4 genome AF: 0.000736 AC: 112AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66AN XY: 74428
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 28, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2020 | Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | NRXN1: BP4, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 11, 2024 | - - |
Pitt-Hopkins-like syndrome 2 Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Aug 05, 2021 | This sequence variant is a single nucleotide substitution (A>T) 5 base pairs downstream of exon 8 of NRXN1. This is a previously reported variant (ClinVar) that has been reported under a different transcript as c.1158+26A>T. To our knowledge, this variant has not been previously reported in individuals with NRXN1-related disease in the literature and is present in control population datasets (gnomAD database 207/205140 alleles or 0.1%). Bioinformatic tools do not predict a significant effect on splicing; however, this residue is well conserved among the vertebrate species examined. Splicing studies confirming an effect of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2025 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2020 | The c.1278+5A>T intronic alteration consists of an A to T substitution 5 nucleotides after exon 8 (coding exon 7) in the NRXN1 gene. Based on data from the Genome Aggregation Database (gnomAD) database, the NRXN1 c.1278+5A>T alteration was observed in 0.1% (207/205140) of total alleles studied, with a frequency of 0.37% (84/22894) in the South Asian subpopulation. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
not specified Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 12, 2018 | - - |
NRXN1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 07, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at