rs483589

Positions:

• chr12-117343726-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.-420-12237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,064 control chromosomes in the GnomAD database, including 10,517 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 0.37 (10517 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0560

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-420-12237C>T		intron_variant		ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-420-12237C>T		intron_variant			NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.-420-12237C>T		intron_variant		1	NM_000620.5	ENSP00000320758	P1
NOS1	ENST00000618760.4	c.-420-12237C>T		intron_variant		5		ENSP00000477999
NOS1	ENST00000549189.1	n.471-12237C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55877 AN: 151946 Hom.: 10505 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.368 AC: 55917 AN: 152064 Hom.: 10517 Cov.: 33 AF XY: 0.367 AC XY: 27312 AN XY: 74328

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.388

Alfa AF: 0.382 Hom.: 11424

Bravo AF: 0.369

Asia WGS AF: 0.307 AC: 1069 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.66

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: rs483589; hg19: chr12-117781531;