12-117232493-C-G

Variant names:

• chr12-117232493-C-G
• rs9658490
• NM_000620.5:c.3236-362G>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.3236-362G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,080 control chromosomes in the GnomAD database, including 2,867 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 0.17 (2867 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3236-362G>C		intron_variant	Intron 21 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3338-362G>C		intron_variant	Intron 22 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2228-362G>C		intron_variant	Intron 20 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2228-362G>C		intron_variant	Intron 20 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3236-362G>C		intron_variant	Intron 21 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3338-362G>C		intron_variant	Intron 21 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3338-362G>C		intron_variant	Intron 22 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26190 AN: 151962 Hom.: 2859 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.0890

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0796

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.172 AC: 26225 AN: 152080 Hom.: 2867 Cov.: 32 AF XY: 0.172 AC XY: 12804 AN XY: 74362

African (AFR) AF: 0.249 AC: 10317 AN: 41462

American (AMR) AF: 0.314 AC: 4798 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3470

East Asian (EAS) AF: 0.0892 AC: 462 AN: 5178

South Asian (SAS) AF: 0.185 AC: 887 AN: 4806

European-Finnish (FIN) AF: 0.0796 AC: 843 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8146 AN: 67994

Other (OTH) AF: 0.164 AC: 347 AN: 2110

Alfa AF: 0.0600 Hom.: 68

Bravo AF: 0.196

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.83
DANN	Benign	0.56
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: rs9658490; hg19: chr12-117670298;