rs12424669

Variant names:

• chr12-117341151-C-T
• rs12424669
• NM_000620.5:c.-420-9662G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.-420-9662G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,158 control chromosomes in the GnomAD database, including 1,067 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1067 hom., cov: 30)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-420-9662G>A		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-420-9662G>A		intron_variant	Intron 1 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.-420-9662G>A		intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000618760.4	c.-420-9662G>A		intron_variant	Intron 1 of 29	5		ENSP00000477999.1
NOS1	ENST00000549189.1	n.471-9662G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16536 AN: 152042 Hom.: 1064 Cov.: 30

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.0642

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.102

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.109 AC: 16540 AN: 152158 Hom.: 1067 Cov.: 30 AF XY: 0.107 AC XY: 7951 AN XY: 74386

African (AFR) AF: 0.0530 AC: 2199 AN: 41502

American (AMR) AF: 0.187 AC: 2853 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3472

East Asian (EAS) AF: 0.0915 AC: 474 AN: 5182

South Asian (SAS) AF: 0.0645 AC: 310 AN: 4806

European-Finnish (FIN) AF: 0.102 AC: 1077 AN: 10596

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8949 AN: 68002

Other (OTH) AF: 0.102 AC: 215 AN: 2110

Alfa AF: 0.127 Hom.: 555

Bravo AF: 0.117

Asia WGS AF: 0.0850 AC: 298 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	6.0
DANN	Benign	0.72
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12424669; hg19: chr12-117778956;