12-117341694-G-A

Variant names:

• chr12-117341694-G-A
• rs499776
• NM_000620.5:c.-420-10205C>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.-420-10205C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 151,942 control chromosomes in the GnomAD database, including 9,549 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 0.35 (9549 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.181
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.-420-10205C>T		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.-420-10205C>T		intron	N/A	NP_001191147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-420-10205C>T		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000618760.4	TSL:5	c.-420-10205C>T		intron	N/A	ENSP00000477999.1
	NOS1	ENST00000549189.1	TSL:3	n.471-10205C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52869 AN: 151824 Hom.: 9538 Cov.: 31

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.375

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

GnomAD4 genome AF: 0.348 AC: 52897 AN: 151942 Hom.: 9549 Cov.: 31 AF XY: 0.346 AC XY: 25701 AN XY: 74238

African (AFR) AF: 0.296 AC: 12243 AN: 41426

American (AMR) AF: 0.372 AC: 5682 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1490 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1115 AN: 5172

South Asian (SAS) AF: 0.326 AC: 1566 AN: 4810

European-Finnish (FIN) AF: 0.358 AC: 3780 AN: 10548

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

European-Non Finnish (NFE) AF: 0.376 AC: 25571 AN: 67954

Other (OTH) AF: 0.372 AC: 781 AN: 2102

Alfa AF: 0.361 Hom.: 4141

Bravo AF: 0.348

Asia WGS AF: 0.281 AC: 975 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.8
DANN	Benign	0.38
PhyloP100		0.18
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: rs499776; hg19: chr12-117779499;