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

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1696563).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRXN1NM_001330078.2 linkc.4237G>A p.Gly1413Ser missense_variant Exon 23 of 23 ENST00000401669.7 NP_001317007.1 E7ERL8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRXN1ENST00000401669.7 linkc.4237G>A p.Gly1413Ser missense_variant Exon 23 of 23 5 NM_001330078.2 ENSP00000385017.2 E7ERL8

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000480
AC:
12
AN:
250170
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
135270
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000709
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000547
AC:
80
AN:
1461678
Hom.:
0
Cov.:
31
AF XY:
0.0000495
AC XY:
36
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000688
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Uncertain:2
May 29, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 06, 2014
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Dec 17, 2022
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
Nov 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Benign
0.49
DEOGEN2
Benign
0.011
.;T;T;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-0.34
.;.;.;.;.;N;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.40
.;N;.;N;N;N;.;.;.;N;.;.;.
REVEL
Benign
0.22
Sift
Benign
0.70
.;T;.;D;T;T;.;.;.;T;.;.;.
Sift4G
Benign
0.71
T;T;.;T;T;T;T;T;T;T;T;T;T
Polyphen
0.056
.;.;.;.;B;.;.;.;.;.;.;.;.
Vest4
0.13
MVP
0.93
MPC
0.78
ClinPred
0.18
T
GERP RS
6.0
Varity_R
0.080
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200604893; hg19: chr2-50149369; COSMIC: COSV60516459; API