rs202006815
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001330078.2(NRXN1):c.4060A>T(p.Thr1354Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,024 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
NRXN1
NM_001330078.2 missense
NM_001330078.2 missense
Scores
1
6
7
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.010817081).
BP6
?
Variant 2-50053339-T-A is Benign according to our data. Variant chr2-50053339-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/152290) while in subpopulation EAS AF= 0.00348 (18/5174). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.4060A>T | p.Thr1354Ser | missense_variant | 21/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.4060A>T | p.Thr1354Ser | missense_variant | 21/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000239 AC: 60AN: 251128Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135728
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GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461734Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47AN XY: 727158
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2019 | The p.T1394S variant (also known as c.4180A>T), located in coding exon 21 of the NRXN1 gene, results from an A to T substitution at nucleotide position 4180. The threonine at codon 1394 is replaced by serine, an amino acid with similar properties. This variant was reported in one Korean individual with juvenile myoclonic epilepsy; additional variants of unknown significance were identified in the JRK and CHRN4A genes (Lee CG et al. PLoS ONE, 2018 Jun;13:e0199321). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Pitt-Hopkins-like syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2020 | This variant is associated with the following publications: (PMID: 33343614, 28785396) - |
Pitt-Hopkins-like syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
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
MutationTaster
Benign
N;N;N;N;N;N;N;N
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;T;D;T;D;D;D;D
Polyphen
0.14
.;.;B;.;.;.;.;.;.;.
Vest4
MutPred
0.21
.;Gain of glycosylation at T1324 (P = 0.043);.;.;.;.;.;.;.;.;
MVP
MPC
1.4
ClinPred
T
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