12-117215033-G-A

Variant names:

• chr12-117215033-G-A
• rs2682826
• NM_000620.5:c.*276C>T

Variant summary

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

The NM_000620.5(NOS1):​c.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,182,334 control chromosomes in the GnomAD database, including 43,705 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 0.25 (5037 hom., cov: 33)
  • Exomes 𝑓: 0.27 (38668 hom.)
• Consequence: NOS1 NM_000620.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 76 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.*276C>T		3_prime_UTR	Exon 29 of 29	NP_000611.1
	NOS1	NM_001204218.2		c.*276C>T		3_prime_UTR	Exon 30 of 30	NP_001191147.1
	NOS1	NM_001204213.2		c.*276C>T		3_prime_UTR	Exon 28 of 28	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.*276C>T		3_prime_UTR	Exon 29 of 29	ENSP00000320758.6
	NOS1	ENST00000618760.4	TSL:5	c.*276C>T		3_prime_UTR	Exon 30 of 30	ENSP00000477999.1
	NOS1	ENST00000338101.8	TSL:5	c.*276C>T		downstream_gene	N/A	ENSP00000337459.4

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38483 AN: 152068 Hom.: 5030 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.272 AC: 280463 AN: 1030148 Hom.: 38668 Cov.: 34 AF XY: 0.273 AC XY: 132299 AN XY: 484386

African (AFR) AF: 0.193 AC: 4197 AN: 21800

American (AMR) AF: 0.244 AC: 1632 AN: 6676

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 4037 AN: 12822

East Asian (EAS) AF: 0.338 AC: 7520 AN: 22242

South Asian (SAS) AF: 0.249 AC: 4551 AN: 18256

European-Finnish (FIN) AF: 0.302 AC: 5008 AN: 16590

Middle Eastern (MID) AF: 0.344 AC: 919 AN: 2670

European-Non Finnish (NFE) AF: 0.272 AC: 241307 AN: 888600

Other (OTH) AF: 0.279 AC: 11292 AN: 40492

GnomAD4 genome AF: 0.253 AC: 38511 AN: 152186 Hom.: 5037 Cov.: 33 AF XY: 0.256 AC XY: 19036 AN XY: 74396

African (AFR) AF: 0.190 AC: 7869 AN: 41524

American (AMR) AF: 0.248 AC: 3798 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3472

East Asian (EAS) AF: 0.322 AC: 1667 AN: 5172

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4812

European-Finnish (FIN) AF: 0.291 AC: 3088 AN: 10594

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18911 AN: 68006

Other (OTH) AF: 0.281 AC: 593 AN: 2112

Alfa AF: 0.271 Hom.: 10246

Bravo AF: 0.245

Asia WGS AF: 0.321 AC: 1114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.52
DANN	Benign	0.83
PhyloP100		-0.41
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: rs2682826; hg19: chr12-117652838;