12-117227508-T-C

Position:

• chr12-117227508-T-C

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.3539A>G​(p.Tyr1180Cys) variant causes a missense change involving the alteration of a 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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 in gene, where missense usually causes diseases (based on misZ statistic), NOS1. . Gene score misZ 3.6832 (greater than the threshold 3.09). Trascript score misZ 4.7179 (greater than threshold 3.09). GenCC has associacion of gene with idiopathic achalasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3539A>G	p.Tyr1180Cys	missense_variant	23/29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3641A>G	p.Tyr1214Cys	missense_variant	24/30		NP_001191147.1
NOS1	NM_001204213.2	c.2531A>G	p.Tyr844Cys	missense_variant	22/28		NP_001191142.1
NOS1	NM_001204214.2	c.2531A>G	p.Tyr844Cys	missense_variant	22/28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3539A>G	p.Tyr1180Cys	missense_variant	23/29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3641A>G	p.Tyr1214Cys	missense_variant	23/29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3641A>G	p.Tyr1214Cys	missense_variant	24/30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Ambry Genetics

Nov 23, 2024

The c.3641A>G (p.Y1214C) alteration is located in exon 24 (coding exon 23) of the NOS1 gene. This alteration results from a A to G substitution at nucleotide position 3641, causing the tyrosine (Y) at amino acid position 1214 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.0	H;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.5	D;.;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0050	D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.72		Gain of catalytic residue at S1184 (P = 4e-04);.;.;.;
MVP		0.89
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-117665313;