rs201802152
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001135659.3(NRXN1):c.1278+5A>T variant causes a splice region, 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001135659.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000736 AC: 112AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00112 AC: 195AN: 173744Hom.: 0 AF XY: 0.00137 AC XY: 125AN XY: 91416
GnomAD4 exome AF: 0.000934 AC: 1310AN: 1402104Hom.: 4 Cov.: 28 AF XY: 0.00106 AC XY: 731AN XY: 692540
GnomAD4 genome AF: 0.000736 AC: 112AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66AN XY: 74428
ClinVar
Submissions by phenotype
not provided Benign:6
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Has not been previously published as pathogenic or benign to our knowledge -
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NRXN1: BP4, BS1 -
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Pitt-Hopkins-like syndrome 2 Uncertain:1Benign:2
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 -
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. -
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Inborn genetic diseases Uncertain:1
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
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not specified Benign:1
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NRXN1-related disorder Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at