12-117246975-G-T

Variant names:

• chr12-117246975-G-T
• rs816353
• NM_000620.5:c.2823+373C>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.2823+373C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,960 control chromosomes in the GnomAD database, including 25,210 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 (25210 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.234
• Publications: 12 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 (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.2823+373C>A		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2925+373C>A		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1815+373C>A		intron	N/A	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2823+373C>A		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2925+373C>A		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2925+373C>A		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83132 AN: 151840 Hom.: 25145 Cov.: 31

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.532

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

GnomAD4 genome AF: 0.548 AC: 83259 AN: 151960 Hom.: 25210 Cov.: 31 AF XY: 0.548 AC XY: 40702 AN XY: 74246

African (AFR) AF: 0.808 AC: 33502 AN: 41480

American (AMR) AF: 0.621 AC: 9477 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1476 AN: 3468

East Asian (EAS) AF: 0.625 AC: 3218 AN: 5150

South Asian (SAS) AF: 0.460 AC: 2215 AN: 4812

European-Finnish (FIN) AF: 0.377 AC: 3972 AN: 10526

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27748 AN: 67944

Other (OTH) AF: 0.536 AC: 1132 AN: 2112

Alfa AF: 0.452 Hom.: 69032

Bravo AF: 0.580

Asia WGS AF: 0.567 AC: 1972 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.71
DANN	Benign	0.52
PhyloP100		-0.23
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: rs816353; hg19: chr12-117684780;