rs2293052

Positions:

• chr12-117277815-G-A

Variant summary

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

The NM_000620.5(NOS1):​c.1664+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 950,458 control chromosomes in the GnomAD database, including 56,828 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 0.28 (7001 hom., cov: 31)
  • Exomes 𝑓: 0.35 (49827 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1664+144C>T		intron_variant		ENST00000317775.11	NP_000611.1
NOS1	NM_001204213.2	c.656+144C>T		intron_variant			NP_001191142.1
NOS1	NM_001204214.2	c.656+144C>T		intron_variant			NP_001191143.1
NOS1	NM_001204218.2	c.1664+144C>T		intron_variant			NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1664+144C>T		intron_variant		1	NM_000620.5	ENSP00000320758	P1
NOS1	ENST00000338101.8	c.1664+144C>T		intron_variant		5		ENSP00000337459
NOS1	ENST00000618760.4	c.1664+144C>T		intron_variant		5		ENSP00000477999

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42409 AN: 151792 Hom.: 7001 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.302

GnomAD4 exome AF: 0.347 AC: 277154 AN: 798548 Hom.: 49827 AF XY: 0.348 AC XY: 140213 AN XY: 403434

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.338

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.279 AC: 42407 AN: 151910 Hom.: 7001 Cov.: 31 AF XY: 0.281 AC XY: 20879 AN XY: 74218

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.300

Alfa AF: 0.323 Hom.: 1075

Bravo AF: 0.261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs2293052; hg19: chr12-117715620; COSMIC: COSV57621377;