12-117281017-C-T

Variant names:

• chr12-117281017-C-T
• rs2293050
• NM_000620.5:c.1383-151G>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.1383-151G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 773,530 control chromosomes in the GnomAD database, including 75,120 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 0.41 (12931 hom., cov: 32)
  • Exomes 𝑓: 0.44 (62189 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 16 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1383-151G>A		intron_variant	Intron 7 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1383-151G>A		intron_variant	Intron 7 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.375-151G>A		intron_variant	Intron 6 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.375-151G>A		intron_variant	Intron 6 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1383-151G>A		intron_variant	Intron 7 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1383-151G>A		intron_variant	Intron 6 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1383-151G>A		intron_variant	Intron 7 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61539 AN: 151656 Hom.: 12925 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.441 AC: 274048 AN: 621756 Hom.: 62189 AF XY: 0.442 AC XY: 140912 AN XY: 318694

African (AFR) AF: 0.310 AC: 4888 AN: 15746

American (AMR) AF: 0.564 AC: 10818 AN: 19190

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 6498 AN: 14754

East Asian (EAS) AF: 0.446 AC: 13979 AN: 31346

South Asian (SAS) AF: 0.488 AC: 23653 AN: 48450

European-Finnish (FIN) AF: 0.397 AC: 13677 AN: 34432

Middle Eastern (MID) AF: 0.330 AC: 816 AN: 2472

European-Non Finnish (NFE) AF: 0.439 AC: 186159 AN: 423938

Other (OTH) AF: 0.431 AC: 13560 AN: 31428

GnomAD4 genome AF: 0.406 AC: 61576 AN: 151774 Hom.: 12931 Cov.: 32 AF XY: 0.406 AC XY: 30102 AN XY: 74162

African (AFR) AF: 0.314 AC: 12998 AN: 41366

American (AMR) AF: 0.511 AC: 7803 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1541 AN: 3470

East Asian (EAS) AF: 0.410 AC: 2100 AN: 5118

South Asian (SAS) AF: 0.495 AC: 2382 AN: 4808

European-Finnish (FIN) AF: 0.397 AC: 4182 AN: 10528

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.431 AC: 29295 AN: 67908

Other (OTH) AF: 0.409 AC: 862 AN: 2108

Alfa AF: 0.406 Hom.: 6352

Bravo AF: 0.410

Asia WGS AF: 0.423 AC: 1474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.088
DANN	Benign	0.81
PhyloP100		-3.2
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: rs2293050; hg19: chr12-117718822;