12-117257515-C-T

Variant names:

• chr12-117257515-C-T
• rs1093325
• NM_000620.5:c.2531+882G>A

Variant summary

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

The NM_000620.5(NOS1):​c.2531+882G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 151,060 control chromosomes in the GnomAD database, including 742 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 0.097 (742 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2531+882G>A		intron_variant	Intron 16 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2531+882G>A		intron_variant	Intron 16 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1523+882G>A		intron_variant	Intron 15 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1523+882G>A		intron_variant	Intron 15 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2531+882G>A		intron_variant	Intron 16 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2531+882G>A		intron_variant	Intron 15 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2531+882G>A		intron_variant	Intron 16 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 14660 AN: 150982 Hom.: 740 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0705

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.0715

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.0872

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

GnomAD4 genome AF: 0.0971 AC: 14672 AN: 151060 Hom.: 742 Cov.: 32 AF XY: 0.0985 AC XY: 7257 AN XY: 73680

African (AFR) AF: 0.104 AC: 4307 AN: 41216

American (AMR) AF: 0.0687 AC: 1042 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.0717 AC: 368 AN: 5136

South Asian (SAS) AF: 0.113 AC: 540 AN: 4776

European-Finnish (FIN) AF: 0.145 AC: 1467 AN: 10114

Middle Eastern (MID) AF: 0.0310 AC: 9 AN: 290

European-Non Finnish (NFE) AF: 0.0953 AC: 6471 AN: 67878

Other (OTH) AF: 0.0856 AC: 180 AN: 2102

Alfa AF: 0.0875 Hom.: 632

Bravo AF: 0.0918

Asia WGS AF: 0.0790 AC: 273 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.65
PhyloP100		0.37
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: rs1093325; hg19: chr12-117695320;