rs816361

Variant names:

• chr12-117217326-C-G
• rs816361
• NM_000620.5:c.4289+720G>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.4289+720G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 152,000 control chromosomes in the GnomAD database, including 5,469 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 0.27 (5469 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 10 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 (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4289+720G>C		intron_variant	Intron 28 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4391+720G>C		intron_variant	Intron 29 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.3281+720G>C		intron_variant	Intron 27 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.3281+720G>C		intron_variant	Intron 27 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4289+720G>C		intron_variant	Intron 28 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4391+720G>C		intron_variant	Intron 28 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4391+720G>C		intron_variant	Intron 29 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40477 AN: 151882 Hom.: 5462 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.286

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

GnomAD4 genome AF: 0.266 AC: 40505 AN: 152000 Hom.: 5469 Cov.: 31 AF XY: 0.269 AC XY: 19986 AN XY: 74276

African (AFR) AF: 0.228 AC: 9434 AN: 41454

American (AMR) AF: 0.257 AC: 3921 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1135 AN: 3462

East Asian (EAS) AF: 0.332 AC: 1710 AN: 5154

South Asian (SAS) AF: 0.267 AC: 1287 AN: 4826

European-Finnish (FIN) AF: 0.290 AC: 3062 AN: 10554

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.280 AC: 19044 AN: 67972

Other (OTH) AF: 0.291 AC: 616 AN: 2116

Alfa AF: 0.269 Hom.: 671

Bravo AF: 0.261

Asia WGS AF: 0.335 AC: 1161 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	4.3
DANN	Benign	0.78
PhyloP100		-0.20
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: rs816361; hg19: chr12-117655131;