rs2291908

chr12-117247333-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):c.2823+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,555,138 control chromosomes in the GnomAD database, including 80,006 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 0.30 (7571 hom., cov: 30)
  • Exomes 𝑓: 0.32 (72435 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.2823+15A>G		intron_variant		ENST00000317775.11
NOS1	NM_001204213.2	c.1815+15A>G		intron_variant
NOS1	NM_001204214.2	c.1815+15A>G		intron_variant
NOS1	NM_001204218.2	c.2925+15A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.2823+15A>G		intron_variant		1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.2925+15A>G		intron_variant		5
NOS1	ENST00000618760.4	c.2925+15A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45050 AN: 151422 Hom.: 7548 Cov.: 30

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.345 AC: 76325 AN: 221082 Hom.: 14979 AF XY: 0.338 AC XY: 40629 AN XY: 120108

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.496

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.316 AC: 443596 AN: 1403598 Hom.: 72435 Cov.: 29 AF XY: 0.316 AC XY: 219902 AN XY: 696132

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.487

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.298 AC: 45095 AN: 151540 Hom.: 7571 Cov.: 30 AF XY: 0.301 AC XY: 22301 AN XY: 74036

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.340

Alfa AF: 0.314 Hom.: 12894

Bravo AF: 0.312

Asia WGS AF: 0.416 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.9
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2291908; hg19: chr12-117685138; COSMIC: COSV57613555; COSMIC: COSV57613555;