rs2139733

Variant names:

• chr12-117288937-T-A
• rs2139733
• NM_000620.5:c.982-718A>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.982-718A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 151,960 control chromosomes in the GnomAD database, including 12,493 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 0.40 (12493 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 13 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 = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.982-718A>T		intron_variant	Intron 4 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.982-718A>T		intron_variant	Intron 4 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.-27-718A>T		intron_variant	Intron 3 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.-27-718A>T		intron_variant	Intron 3 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.982-718A>T		intron_variant	Intron 4 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.982-718A>T		intron_variant	Intron 3 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.982-718A>T		intron_variant	Intron 4 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60171 AN: 151842 Hom.: 12487 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.396 AC: 60212 AN: 151960 Hom.: 12493 Cov.: 32 AF XY: 0.397 AC XY: 29505 AN XY: 74272

African (AFR) AF: 0.287 AC: 11911 AN: 41452

American (AMR) AF: 0.504 AC: 7700 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3466

East Asian (EAS) AF: 0.408 AC: 2104 AN: 5156

South Asian (SAS) AF: 0.487 AC: 2343 AN: 4816

European-Finnish (FIN) AF: 0.397 AC: 4191 AN: 10544

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29133 AN: 67942

Other (OTH) AF: 0.409 AC: 864 AN: 2114

Alfa AF: 0.408 Hom.: 1616

Bravo AF: 0.400

Asia WGS AF: 0.433 AC: 1509 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.014
DANN	Benign	0.49
PhyloP100		-1.2
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: rs2139733; hg19: chr12-117726742;