rs9658354

Variant names:

• chr12-117286420-A-T
• rs9658354
• NM_000620.5:c.1128-154T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.1128-154T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 152,080 control chromosomes in the GnomAD database, including 13,031 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 0.41 (13031 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1128-154T>A		intron_variant	Intron 5 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1128-154T>A		intron_variant	Intron 5 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.120-154T>A		intron_variant	Intron 4 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.120-154T>A		intron_variant	Intron 4 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1128-154T>A		intron_variant	Intron 5 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1128-154T>A		intron_variant	Intron 4 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1128-154T>A		intron_variant	Intron 5 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61911 AN: 151964 Hom.: 13019 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.407 AC: 61963 AN: 152080 Hom.: 13031 Cov.: 32 AF XY: 0.408 AC XY: 30347 AN XY: 74354

African (AFR) AF: 0.326 AC: 13524 AN: 41478

American (AMR) AF: 0.509 AC: 7763 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1589 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2119 AN: 5176

South Asian (SAS) AF: 0.490 AC: 2357 AN: 4814

European-Finnish (FIN) AF: 0.396 AC: 4191 AN: 10584

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29146 AN: 67978

Other (OTH) AF: 0.417 AC: 880 AN: 2110

Alfa AF: 0.414 Hom.: 1646

Bravo AF: 0.413

Asia WGS AF: 0.429 AC: 1496 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	1.3
DANN	Benign	0.46
PhyloP100		0.28
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: rs9658354; hg19: chr12-117724225;