chr12-117270390-G-A

Variant names:

• chr12-117270390-G-A
• rs6490121
• NM_000620.5:c.1839+1995C>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.1839+1995C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 151,792 control chromosomes in the GnomAD database, including 31,784 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 0.64 (31784 hom., cov: 30)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134
• Publications: 40 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 (SAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1839+1995C>T		intron_variant	Intron 10 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1839+1995C>T		intron_variant	Intron 10 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.831+1995C>T		intron_variant	Intron 9 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.831+1995C>T		intron_variant	Intron 9 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1839+1995C>T		intron_variant	Intron 10 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1839+1995C>T		intron_variant	Intron 9 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1839+1995C>T		intron_variant	Intron 10 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97633 AN: 151674 Hom.: 31759 Cov.: 30

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.644 AC: 97702 AN: 151792 Hom.: 31784 Cov.: 30 AF XY: 0.642 AC XY: 47605 AN XY: 74132

African (AFR) AF: 0.623 AC: 25783 AN: 41382

American (AMR) AF: 0.509 AC: 7747 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2591 AN: 3472

East Asian (EAS) AF: 0.610 AC: 3117 AN: 5114

South Asian (SAS) AF: 0.714 AC: 3433 AN: 4806

European-Finnish (FIN) AF: 0.687 AC: 7220 AN: 10510

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.671 AC: 45631 AN: 67972

Other (OTH) AF: 0.651 AC: 1372 AN: 2106

Alfa AF: 0.654 Hom.: 38823

Bravo AF: 0.626

Asia WGS AF: 0.615 AC: 2140 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.61
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6490121; hg19: chr12-117708195;