rs3782221

Variant names:

• chr12-117358076-G-A
• rs3782221
• NM_000620.5:c.-421+3436C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-117358076-G-A
• chr12-117358076-G-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.-421+3436C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,112 control chromosomes in the GnomAD database, including 5,219 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 0.25 (5219 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 24 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=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 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.-421+3436C>T		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.-421+3436C>T		intron	N/A	NP_001191147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-421+3436C>T		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000618760.4	TSL:5	c.-421+3436C>T		intron	N/A	ENSP00000477999.1
	NOS1	ENST00000477584.1	TSL:2	n.118+3436C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38696 AN: 151992 Hom.: 5212 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.244

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

GnomAD4 genome AF: 0.255 AC: 38722 AN: 152112 Hom.: 5219 Cov.: 33 AF XY: 0.260 AC XY: 19333 AN XY: 74358

African (AFR) AF: 0.264 AC: 10950 AN: 41482

American (AMR) AF: 0.225 AC: 3444 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2648 AN: 5164

South Asian (SAS) AF: 0.325 AC: 1568 AN: 4820

European-Finnish (FIN) AF: 0.291 AC: 3075 AN: 10572

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15600 AN: 68004

Other (OTH) AF: 0.244 AC: 514 AN: 2108

Alfa AF: 0.232 Hom.: 3902

Bravo AF: 0.247

Asia WGS AF: 0.413 AC: 1431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.063
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: rs3782221; hg19: chr12-117795881;