12-117327262-G-A

Variant names:

• chr12-117327262-G-A
• rs1520811
• NM_000620.5:c.725+3083C>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.725+3083C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,164 control chromosomes in the GnomAD database, including 4,712 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 0.23 (4712 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.679
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.725+3083C>T		intron_variant	Intron 2 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.725+3083C>T		intron_variant	Intron 2 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.725+3083C>T		intron_variant	Intron 2 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.725+3083C>T		intron_variant	Intron 1 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.725+3083C>T		intron_variant	Intron 2 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35732 AN: 152046 Hom.: 4715 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.235 AC: 35730 AN: 152164 Hom.: 4712 Cov.: 33 AF XY: 0.232 AC XY: 17276 AN XY: 74384

African (AFR) AF: 0.129 AC: 5345 AN: 41546

American (AMR) AF: 0.278 AC: 4248 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3466

East Asian (EAS) AF: 0.0912 AC: 472 AN: 5176

South Asian (SAS) AF: 0.169 AC: 814 AN: 4822

European-Finnish (FIN) AF: 0.284 AC: 3009 AN: 10598

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20244 AN: 67954

Other (OTH) AF: 0.221 AC: 467 AN: 2114

Alfa AF: 0.263 Hom.: 681

Bravo AF: 0.235

Asia WGS AF: 0.139 AC: 488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		0.68
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: rs1520811; hg19: chr12-117765067;