rs2393207

Variant names:

• chr12-117264979-A-T
• rs2393207
• NM_000620.5:c.2136+337T>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.2136+337T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 151,196 control chromosomes in the GnomAD database, including 17,002 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 0.45 (17002 hom., cov: 27)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• Publications: 2 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.2136+337T>A		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2136+337T>A		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1128+337T>A		intron	N/A	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2136+337T>A		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2136+337T>A		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2136+337T>A		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 67904 AN: 151078 Hom.: 17006 Cov.: 27

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.464

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

GnomAD4 genome AF: 0.449 AC: 67901 AN: 151196 Hom.: 17002 Cov.: 27 AF XY: 0.450 AC XY: 33253 AN XY: 73820

African (AFR) AF: 0.231 AC: 9505 AN: 41192

American (AMR) AF: 0.383 AC: 5821 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2166 AN: 3464

East Asian (EAS) AF: 0.424 AC: 2153 AN: 5082

South Asian (SAS) AF: 0.556 AC: 2640 AN: 4750

European-Finnish (FIN) AF: 0.589 AC: 6157 AN: 10446

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37800 AN: 67774

Other (OTH) AF: 0.460 AC: 964 AN: 2094

Alfa AF: 0.495 Hom.: 2441

Bravo AF: 0.422

Asia WGS AF: 0.454 AC: 1577 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.3
DANN	Benign	0.95
PhyloP100		0.30
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: rs2393207; hg19: chr12-117702784;