rs201963074
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_001330078.2(NRXN1):āc.3281A>Gā(p.Asn1094Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.000017 ( 0 hom. )
Consequence
NRXN1
NM_001330078.2 missense
NM_001330078.2 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 8.02
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 Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.884
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.3281A>G | p.Asn1094Ser | missense_variant | 17/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.3281A>G | p.Asn1094Ser | missense_variant | 17/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151868Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246824Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133892
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1458792Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 725628
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GnomAD4 genome AF: 0.0000198 AC: 3AN: 151868Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74174
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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 | Oct 21, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Has not been previously published as pathogenic or benign to our knowledge - |
Pitt-Hopkins-like syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1134 of the NRXN1 protein (p.Asn1134Ser). This variant is present in population databases (rs201963074, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206260). 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 disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;H;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;D;D;.;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.;.
Vest4
MVP
MPC
0.66
ClinPred
D
GERP RS
Varity_R
gMVP
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