rs816354

Variant names:

• chr12-117246911-A-G
• rs816354
• NM_000620.5:c.2823+437T>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.2823+437T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 152,198 control chromosomes in the GnomAD database, including 467 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 (467 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• Publications: 6 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2823+437T>C		intron_variant	Intron 18 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2925+437T>C		intron_variant	Intron 19 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1815+437T>C		intron_variant	Intron 17 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1815+437T>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.2823+437T>C		intron_variant	Intron 18 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2925+437T>C		intron_variant	Intron 18 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2925+437T>C		intron_variant	Intron 19 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11486 AN: 152080 Hom.: 466 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0689

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

GnomAD4 genome AF: 0.0755 AC: 11491 AN: 152198 Hom.: 467 Cov.: 32 AF XY: 0.0776 AC XY: 5775 AN XY: 74434

African (AFR) AF: 0.0716 AC: 2971 AN: 41516

American (AMR) AF: 0.0589 AC: 900 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3472

East Asian (EAS) AF: 0.0775 AC: 402 AN: 5184

South Asian (SAS) AF: 0.0674 AC: 325 AN: 4820

European-Finnish (FIN) AF: 0.133 AC: 1409 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5174 AN: 68006

Other (OTH) AF: 0.0672 AC: 142 AN: 2112

Alfa AF: 0.0742 Hom.: 59

Bravo AF: 0.0715

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.8
DANN	Benign	0.86
PhyloP100		0.14
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: rs816354; hg19: chr12-117684716;