1-162287434-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014697.3(NOS1AP):​c.268A>G​(p.Lys90Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NOS1AP
NM_014697.3 missense, splice_region

Scores

2
8
9
Splicing: ADA: 0.1970
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.24
Variant links:
Genes affected
NOS1AP (HGNC:16859): (nitric oxide synthase 1 adaptor protein) This gene encodes a cytosolic protein that binds to the signaling molecule, neuronal nitric oxide synthase (nNOS). This protein has a C-terminal PDZ-binding domain that mediates interactions with nNOS and an N-terminal phosphotyrosine binding (PTB) domain that binds to the small monomeric G protein, Dexras1. Studies of the related mouse and rat proteins have shown that this protein functions as an adapter protein linking nNOS to specific targets, such as Dexras1 and the synapsins. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35862136).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOS1APNM_014697.3 linkc.268A>G p.Lys90Glu missense_variant, splice_region_variant Exon 3 of 10 ENST00000361897.10 NP_055512.1 O75052-1
NOS1APNM_001164757.2 linkc.268A>G p.Lys90Glu missense_variant, splice_region_variant Exon 3 of 10 NP_001158229.1 O75052-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOS1APENST00000361897.10 linkc.268A>G p.Lys90Glu missense_variant, splice_region_variant Exon 3 of 10 1 NM_014697.3 ENSP00000355133.5 O75052-1
NOS1APENST00000530878.5 linkc.268A>G p.Lys90Glu missense_variant, splice_region_variant Exon 3 of 10 1 ENSP00000431586.1 O75052-3
NOS1APENST00000430120.3 linkn.268A>G splice_region_variant, non_coding_transcript_exon_variant Exon 3 of 11 1 ENSP00000396713.3 E9PSG0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 15, 2016
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
.;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.32
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;M
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Benign
0.19
Sift
Benign
0.035
D;T
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.92
.;P
Vest4
0.46
MutPred
0.45
Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);
MVP
0.49
MPC
2.6
ClinPred
0.98
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.52
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.20
dbscSNV1_RF
Benign
0.42
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: rs1215631561; hg19: chr1-162257224; API