rs7308402

Variant names:

• chr12-117321642-G-A
• rs7308402
• NM_000620.5:c.725+8703C>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+8703C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 151,968 control chromosomes in the GnomAD database, including 5,668 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 0.26 (5668 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 5 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 = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.725+8703C>T		intron_variant	Intron 2 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.725+8703C>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+8703C>T		intron_variant	Intron 2 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.725+8703C>T		intron_variant	Intron 1 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.725+8703C>T		intron_variant	Intron 2 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38864 AN: 151850 Hom.: 5670 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.256 AC: 38883 AN: 151968 Hom.: 5668 Cov.: 31 AF XY: 0.252 AC XY: 18705 AN XY: 74244

African (AFR) AF: 0.135 AC: 5583 AN: 41458

American (AMR) AF: 0.304 AC: 4648 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.0362 AC: 187 AN: 5172

South Asian (SAS) AF: 0.193 AC: 929 AN: 4812

European-Finnish (FIN) AF: 0.300 AC: 3162 AN: 10540

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22370 AN: 67936

Other (OTH) AF: 0.244 AC: 514 AN: 2106

Alfa AF: 0.299 Hom.: 2714

Bravo AF: 0.256

Asia WGS AF: 0.132 AC: 465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.61
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: rs7308402; hg19: chr12-117759447;