12-117285808-A-G

Variant names:

• chr12-117285808-A-G
• rs884847
• NM_000620.5:c.1290+296T>C

Variant summary

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

The NM_000620.5(NOS1):​c.1290+296T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 152,146 control chromosomes in the GnomAD database, including 51,515 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 0.82 (51515 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 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.1290+296T>C		intron	N/A	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.1290+296T>C		intron	N/A	NP_001191147.1	P29475-5
	NOS1	NM_001204213.2		c.282+296T>C		intron	N/A	NP_001191142.1	P29475-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.1290+296T>C		intron	N/A	ENSP00000320758.6	P29475-1
	NOS1	ENST00000338101.8	TSL:5	c.1290+296T>C		intron	N/A	ENSP00000337459.4	P29475-5
	NOS1	ENST00000618760.4	TSL:5	c.1290+296T>C		intron	N/A	ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124994 AN: 152030 Hom.: 51473 Cov.: 32

Gnomad AFR AF: 0.874

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.815

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

GnomAD4 genome AF: 0.822 AC: 125091 AN: 152146 Hom.: 51515 Cov.: 32 AF XY: 0.821 AC XY: 61047 AN XY: 74354

African (AFR) AF: 0.874 AC: 36275 AN: 41502

American (AMR) AF: 0.822 AC: 12563 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2794 AN: 3472

East Asian (EAS) AF: 0.851 AC: 4400 AN: 5172

South Asian (SAS) AF: 0.845 AC: 4071 AN: 4818

European-Finnish (FIN) AF: 0.780 AC: 8262 AN: 10586

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 54025 AN: 68004

Other (OTH) AF: 0.814 AC: 1716 AN: 2108

Alfa AF: 0.803 Hom.: 42875

Bravo AF: 0.829

Asia WGS AF: 0.803 AC: 2795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.46
PhyloP100		0.14
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: rs884847; hg19: chr12-117723613;