rs770641207
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_001330078.2(NRXN1):c.374A>G(p.Asn125Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 1,610,658 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
NRXN1
NM_001330078.2 missense
NM_001330078.2 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 6.08
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 Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.29321665).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.374A>G | p.Asn125Ser | missense_variant | 2/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.374A>G | p.Asn125Ser | missense_variant | 2/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000205 AC: 5AN: 243416Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132930
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GnomAD4 exome AF: 0.00000754 AC: 11AN: 1458482Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 725772
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2018 | The Asn125Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Asn125Ser alters a well conserved position in the Laminin G domain of the Neurexin-1 protein. However, the amino acid substitution is conservative as both Asparagine and Serine are uncharged, polar amino acid residues. In addition, several in-silico algorithms predict Asn125Ser may be benign. Therefore, based on the currently available information, it is unclear whether Asn125Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Pitt-Hopkins-like syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 125 of the NRXN1 protein (p.Asn125Ser). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 206238). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. This variant is present in population databases (rs770641207, gnomAD 0.01%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.;T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;.;.;.;.;.;.
MutationTaster
Benign
N;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;N;N;.;.;N;.;.
REVEL
Uncertain
Sift
Benign
.;T;T;T;T;.;.;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;T;.;T
Polyphen
0.012, 0.11
.;B;B;.;.;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP
MPC
0.55
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at