rs2293054

Positions:

• chr12-117263909-A-C
• chr12-117263909-A-G
• chr12-117263909-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000620.5(NOS1):​c.2202T>G​(p.Ile734Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I734I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.374

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NOS1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.2202T>G	p.Ile734Met	missense_variant	13/29	ENST00000317775.11
NOS1	NM_001204218.2	c.2202T>G	p.Ile734Met	missense_variant	13/30
NOS1	NM_001204213.2	c.1194T>G	p.Ile398Met	missense_variant	12/28
NOS1	NM_001204214.2	c.1194T>G	p.Ile398Met	missense_variant	12/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.2202T>G	p.Ile734Met	missense_variant	13/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.2202T>G	p.Ile734Met	missense_variant	12/29	5
NOS1	ENST00000618760.4	c.2202T>G	p.Ile734Met	missense_variant	13/30	5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	0.000010	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;.;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.017	D;.;D;.
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.70
MutPred		0.42		Gain of catalytic residue at K730 (P = 0);Gain of catalytic residue at K730 (P = 0);Gain of catalytic residue at K730 (P = 0);.;
MVP		0.50
MPC		0.95
ClinPred		0.89	D
GERP RS		-3.9
Varity_R		0.22
gMVP		0.64

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: rs2293054; hg19: chr12-117701714;