NM_000620.5:c.852+1584G>A

Variant names:

• chr12-117309882-C-T
• rs11068447
• NM_000620.5:c.852+1584G>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.852+1584G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,138 control chromosomes in the GnomAD database, including 1,634 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 0.14 (1634 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.415
• Publications: 9 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 (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.852+1584G>A		intron_variant	Intron 3 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.852+1584G>A		intron_variant	Intron 3 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.852+1584G>A		intron_variant	Intron 3 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.852+1584G>A		intron_variant	Intron 2 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.852+1584G>A		intron_variant	Intron 3 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20659 AN: 152020 Hom.: 1633 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.136 AC: 20672 AN: 152138 Hom.: 1634 Cov.: 33 AF XY: 0.140 AC XY: 10394 AN XY: 74374

African (AFR) AF: 0.112 AC: 4659 AN: 41516

American (AMR) AF: 0.192 AC: 2932 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3468

East Asian (EAS) AF: 0.264 AC: 1362 AN: 5166

South Asian (SAS) AF: 0.251 AC: 1210 AN: 4828

European-Finnish (FIN) AF: 0.112 AC: 1182 AN: 10574

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8474 AN: 67996

Other (OTH) AF: 0.145 AC: 307 AN: 2112

Alfa AF: 0.129 Hom.: 1136

Bravo AF: 0.137

Asia WGS AF: 0.230 AC: 798 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	4.8
DANN	Benign	0.83
PhyloP100		-0.41
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: rs11068447; hg19: chr12-117747687;