rs1158884387

Variant names:

• chr12-117222812-A-G
• rs1158884387
• NM_000620.5:c.3878T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-117222812-A-G
• chr12-117222812-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000620.5(NOS1):​c.3878T>C​(p.Ile1293Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36
• Publications: 0 publications found

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]

NOS1 Gene-Disease associations (from GenCC):

• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2589971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3878T>C	p.Ile1293Thr	missense_variant	Exon 26 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3980T>C	p.Ile1327Thr	missense_variant	Exon 27 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2870T>C	p.Ile957Thr	missense_variant	Exon 25 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2870T>C	p.Ile957Thr	missense_variant	Exon 25 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3878T>C	p.Ile1293Thr	missense_variant	Exon 26 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3980T>C	p.Ile1327Thr	missense_variant	Exon 26 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3980T>C	p.Ile1327Thr	missense_variant	Exon 27 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3980T>C (p.I1327T) alteration is located in exon 27 (coding exon 26) of the NOS1 gene. This alteration results from a T to C substitution at nucleotide position 3980, causing the isoleucine (I) at amino acid position 1327 to be replaced by a threonine (T). 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	Benign	0.12
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.55	D;.;.;T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.0064
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;.;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-1.6	N;.;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;.;D;.
REVEL	Uncertain	0.32
Sift	Benign	0.54	T;.;T;.
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.61	P;.;.;.
Vest4		0.25
MutPred		0.51		Gain of catalytic residue at K1292 (P = 4e-04);.;.;.;
MVP		0.58
MPC		0.71
ClinPred		0.75	D
GERP RS		2.8
Varity_R		0.15
gMVP		0.60
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1158884387; hg19: chr12-117660617;