chr12-117249121-C-G

Variant names:

• chr12-117249121-C-G
• rs2682825
• NM_000620.5:c.2649-1599G>C

Variant summary

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

The NM_000620.5(NOS1):​c.2649-1599G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 151,926 control chromosomes in the GnomAD database, including 25,299 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 0.55 (25299 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2649-1599G>C		intron_variant	Intron 17 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2751-1599G>C		intron_variant	Intron 18 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1641-1599G>C		intron_variant	Intron 16 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1641-1599G>C		intron_variant	Intron 16 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2649-1599G>C		intron_variant	Intron 17 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2751-1599G>C		intron_variant	Intron 17 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2751-1599G>C		intron_variant	Intron 18 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83213 AN: 151808 Hom.: 25226 Cov.: 31

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.549 AC: 83347 AN: 151926 Hom.: 25299 Cov.: 31 AF XY: 0.549 AC XY: 40774 AN XY: 74246

African (AFR) AF: 0.810 AC: 33580 AN: 41446

American (AMR) AF: 0.621 AC: 9492 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1474 AN: 3468

East Asian (EAS) AF: 0.627 AC: 3235 AN: 5156

South Asian (SAS) AF: 0.465 AC: 2237 AN: 4814

European-Finnish (FIN) AF: 0.376 AC: 3950 AN: 10512

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27732 AN: 67932

Other (OTH) AF: 0.535 AC: 1128 AN: 2110

Alfa AF: 0.488 Hom.: 2440

Bravo AF: 0.581

Asia WGS AF: 0.568 AC: 1978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.51
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: rs2682825; hg19: chr12-117686926;