rs1552228

Variant names:

• chr12-117341365-A-G
• rs1552228
• NM_000620.5:c.-420-9876T>C

Variant summary

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

The NM_000620.5(NOS1):​c.-420-9876T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,186 control chromosomes in the GnomAD database, including 1,028 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 0.10 (1028 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• Publications: 4 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 = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-420-9876T>C		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-420-9876T>C		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.-420-9876T>C		intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000618760.4	c.-420-9876T>C		intron_variant	Intron 1 of 29	5		ENSP00000477999.1
NOS1	ENST00000549189.1	n.471-9876T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15757 AN: 152066 Hom.: 1026 Cov.: 31

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.0969

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.0620

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.104 AC: 15756 AN: 152186 Hom.: 1028 Cov.: 31 AF XY: 0.102 AC XY: 7566 AN XY: 74388

African (AFR) AF: 0.0396 AC: 1645 AN: 41546

American (AMR) AF: 0.187 AC: 2860 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0969 AC: 336 AN: 3468

East Asian (EAS) AF: 0.0527 AC: 273 AN: 5180

South Asian (SAS) AF: 0.0625 AC: 301 AN: 4816

European-Finnish (FIN) AF: 0.101 AC: 1068 AN: 10590

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8935 AN: 67996

Other (OTH) AF: 0.100 AC: 212 AN: 2112

Alfa AF: 0.124 Hom.: 278

Bravo AF: 0.111

Asia WGS AF: 0.0700 AC: 245 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	4.3
DANN	Benign	0.47
PhyloP100		-0.12
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: rs1552228; hg19: chr12-117779170;