rs200604893
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001330078.2(NRXN1):c.4237G>A(p.Gly1413Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001330078.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000480 AC: 12AN: 250170Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135270
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461678Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727122
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74312
ClinVar
Submissions by phenotype
Pitt-Hopkins-like syndrome 2 Uncertain:2
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This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1453 of the NRXN1 protein (p.Gly1453Ser). This variant is present in population databases (rs200604893, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of NRXN1-related conditions (PMID: 22504536, 36703223). This variant is also known as c.1132G>A (p.Gly378Ser). ClinVar contains an entry for this variant (Variation ID: 206273). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NRXN1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
This variant p.Gly1453Ser alters both the alpha and beta transcripts of the NRXN1 protein. In the shorter beta-neurexin transcript (NM_128735.2), the variant is denoted p.G348S and has been published using alternative nomeclature (G378S) in a patient with autism, intellectual disability and compulsive personality disorder and his mother who had an unspecified mental disorder (Camacho-Garcia et al., 2012). In the primary transcript (NM_001135659.1) the variant is denoted p.G1453S. Regardless of the transcript, this variant is a non-conservative amino acid substitution that alters a position that is conserved in mammals. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -
not provided Uncertain:1
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Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at