rs527590

Variant names:

• chr12-117344113-T-C
• rs527590
• NM_000620.5:c.-420-12624A>G

Variant summary

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

The NM_000620.5(NOS1):​c.-420-12624A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 152,210 control chromosomes in the GnomAD database, including 52,379 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 0.83 (52379 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-420-12624A>G		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-420-12624A>G		intron_variant	Intron 1 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.-420-12624A>G		intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000618760.4	c.-420-12624A>G		intron_variant	Intron 1 of 29	5		ENSP00000477999.1
NOS1	ENST00000549189.1	n.471-12624A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.825 AC: 125490 AN: 152092 Hom.: 52314 Cov.: 33

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.820

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

GnomAD4 genome AF: 0.825 AC: 125615 AN: 152210 Hom.: 52379 Cov.: 33 AF XY: 0.822 AC XY: 61148 AN XY: 74406

African (AFR) AF: 0.940 AC: 39055 AN: 41560

American (AMR) AF: 0.807 AC: 12336 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2826 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3186 AN: 5170

South Asian (SAS) AF: 0.875 AC: 4214 AN: 4816

European-Finnish (FIN) AF: 0.745 AC: 7874 AN: 10568

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53364 AN: 68022

Other (OTH) AF: 0.820 AC: 1733 AN: 2114

Alfa AF: 0.807 Hom.: 25269

Bravo AF: 0.834

Asia WGS AF: 0.777 AC: 2706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.57
PhyloP100		-0.038
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: rs527590; hg19: chr12-117781918;