rs816347

Variant names:

• chr12-117252118-G-A
• rs816347
• NM_000620.5:c.2648+1520C>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.2648+1520C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 152,146 control chromosomes in the GnomAD database, including 472 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 0.076 (472 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2648+1520C>T		intron_variant	Intron 17 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2750+1520C>T		intron_variant	Intron 18 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1640+1520C>T		intron_variant	Intron 16 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1640+1520C>T		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.2648+1520C>T		intron_variant	Intron 17 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2750+1520C>T		intron_variant	Intron 17 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2750+1520C>T		intron_variant	Intron 18 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11498 AN: 152028 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.0696

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0760

Gnomad OTH AF: 0.0698

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

GnomAD4 genome AF: 0.0756 AC: 11500 AN: 152146 Hom.: 472 Cov.: 32 AF XY: 0.0778 AC XY: 5785 AN XY: 74366

African (AFR) AF: 0.0716 AC: 2973 AN: 41508

American (AMR) AF: 0.0590 AC: 902 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3470

East Asian (EAS) AF: 0.0780 AC: 404 AN: 5178

South Asian (SAS) AF: 0.0695 AC: 335 AN: 4822

European-Finnish (FIN) AF: 0.133 AC: 1406 AN: 10568

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0760 AC: 5169 AN: 68002

Other (OTH) AF: 0.0681 AC: 144 AN: 2114

Alfa AF: 0.0734 Hom.: 213

Bravo AF: 0.0713

Asia WGS AF: 0.0550 AC: 191 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.43
PhyloP100		0.16
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: rs816347; hg19: chr12-117689923;