rs483589

Variant names:

• chr12-117343726-G-A
• rs483589
• NM_000620.5:c.-420-12237C>T

Variant summary

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

The NM_000620.5(NOS1):​c.-420-12237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,064 control chromosomes in the GnomAD database, including 10,517 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 0.37 (10517 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0560
• Publications: 8 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.-420-12237C>T		intron	N/A	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.-420-12237C>T		intron	N/A	NP_001191147.1	P29475-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-420-12237C>T		intron	N/A	ENSP00000320758.6	P29475-1
	NOS1	ENST00000618760.4	TSL:5	c.-420-12237C>T		intron	N/A	ENSP00000477999.1	P29475-5
	NOS1	ENST00000549189.1	TSL:3	n.471-12237C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55877 AN: 151946 Hom.: 10505 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.368 AC: 55917 AN: 152064 Hom.: 10517 Cov.: 33 AF XY: 0.367 AC XY: 27312 AN XY: 74328

African (AFR) AF: 0.334 AC: 13859 AN: 41480

American (AMR) AF: 0.403 AC: 6167 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1462 AN: 3462

East Asian (EAS) AF: 0.261 AC: 1348 AN: 5170

South Asian (SAS) AF: 0.364 AC: 1754 AN: 4822

European-Finnish (FIN) AF: 0.376 AC: 3972 AN: 10562

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25863 AN: 67972

Other (OTH) AF: 0.388 AC: 817 AN: 2108

Alfa AF: 0.378 Hom.: 30406

Bravo AF: 0.369

Asia WGS AF: 0.307 AC: 1069 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		-0.056
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: rs483589; hg19: chr12-117781531;