12-117237548-C-T

Variant names:

• chr12-117237548-C-T
• rs1353939
• NM_000620.5:c.3042-2790G>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.3042-2790G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 151,952 control chromosomes in the GnomAD database, including 3,477 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 0.21 (3477 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 11 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3042-2790G>A		intron_variant	Intron 20 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3144-2790G>A		intron_variant	Intron 21 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2034-2790G>A		intron_variant	Intron 19 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2034-2790G>A		intron_variant	Intron 19 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3042-2790G>A		intron_variant	Intron 20 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3144-2790G>A		intron_variant	Intron 20 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3144-2790G>A		intron_variant	Intron 21 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31554 AN: 151834 Hom.: 3467 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.208 AC: 31584 AN: 151952 Hom.: 3477 Cov.: 32 AF XY: 0.209 AC XY: 15487 AN XY: 74262

African (AFR) AF: 0.205 AC: 8477 AN: 41432

American (AMR) AF: 0.206 AC: 3139 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3470

East Asian (EAS) AF: 0.327 AC: 1686 AN: 5154

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4814

European-Finnish (FIN) AF: 0.155 AC: 1634 AN: 10568

Middle Eastern (MID) AF: 0.341 AC: 99 AN: 290

European-Non Finnish (NFE) AF: 0.203 AC: 13772 AN: 67946

Other (OTH) AF: 0.240 AC: 507 AN: 2112

Alfa AF: 0.208 Hom.: 13443

Bravo AF: 0.209

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.087
DANN	Benign	0.50
PhyloP100		-2.8
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: rs1353939; hg19: chr12-117675353;