rs10850803

Variant names:

• chr12-117244024-A-G
• rs10850803
• NM_000620.5:c.2824-589T>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.2824-589T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,174 control chromosomes in the GnomAD database, including 2,924 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 0.17 (2924 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.706
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2824-589T>C		intron_variant	Intron 18 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2926-589T>C		intron_variant	Intron 19 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1816-589T>C		intron_variant	Intron 17 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1816-589T>C		intron_variant	Intron 17 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2824-589T>C		intron_variant	Intron 18 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2926-589T>C		intron_variant	Intron 18 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2926-589T>C		intron_variant	Intron 19 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25289 AN: 152058 Hom.: 2912 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.148

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

GnomAD4 genome AF: 0.167 AC: 25338 AN: 152174 Hom.: 2924 Cov.: 32 AF XY: 0.166 AC XY: 12338 AN XY: 74396

African (AFR) AF: 0.281 AC: 11677 AN: 41492

American (AMR) AF: 0.307 AC: 4697 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5178

South Asian (SAS) AF: 0.100 AC: 485 AN: 4828

European-Finnish (FIN) AF: 0.0744 AC: 789 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6892 AN: 68014

Other (OTH) AF: 0.148 AC: 312 AN: 2114

Alfa AF: 0.136 Hom.: 3163

Bravo AF: 0.193

Asia WGS AF: 0.100 AC: 351 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	0.99
DANN	Benign	0.57
PhyloP100		-0.71
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: rs10850803; hg19: chr12-117681829;