1-162070269-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014697.3(NOS1AP):c.92G>A(p.Cys31Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOS1AP NM_014697.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20485985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1AP	NM_014697.3	c.92G>A	p.Cys31Tyr	missense_variant	1/10	ENST00000361897.10
NOS1AP	NM_001164757.2	c.92G>A	p.Cys31Tyr	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1AP	ENST00000361897.10	c.92G>A	p.Cys31Tyr	missense_variant	1/10	1	NM_014697.3
NOS1AP	ENST00000530878.5	c.92G>A	p.Cys31Tyr	missense_variant	1/10	1		P1
NOS1AP	ENST00000430120.3	c.92G>A	p.Cys31Tyr	missense_variant, NMD_transcript_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 18, 2019

Variant summary: NOS1AP c.92G>A (p.Cys31Tyr) results in a non-conservative amino acid change located in the PTB/PI domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 243410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.92G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.69	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.092
Sift	Benign	0.51	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.029	.;B
Vest4		0.41
MutPred		0.46		Gain of catalytic residue at I30 (P = 0.0351);Gain of catalytic residue at I30 (P = 0.0351);
MVP		0.26
MPC		1.9
ClinPred		0.067	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.80

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

Other links and lift over

dbSNP: rs1691632353; hg19: chr1-162040059;