NM_000620.5:c.726-5109T>C

Variant names:

• chr12-117316701-A-G
• rs547954
• NM_000620.5:c.726-5109T>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.726-5109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 152,078 control chromosomes in the GnomAD database, including 50,947 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 0.82 (50947 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.612
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.839 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.726-5109T>C		intron	N/A	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.726-5109T>C		intron	N/A	NP_001191147.1	P29475-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.726-5109T>C		intron	N/A	ENSP00000320758.6	P29475-1
	NOS1	ENST00000338101.8	TSL:5	c.726-5109T>C		intron	N/A	ENSP00000337459.4	P29475-5
	NOS1	ENST00000618760.4	TSL:5	c.726-5109T>C		intron	N/A	ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes AF: 0.817 AC: 124163 AN: 151960 Hom.: 50904 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.860

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.815

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

GnomAD4 genome AF: 0.817 AC: 124265 AN: 152078 Hom.: 50947 Cov.: 31 AF XY: 0.815 AC XY: 60612 AN XY: 74326

African (AFR) AF: 0.834 AC: 34604 AN: 41506

American (AMR) AF: 0.826 AC: 12612 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 2983 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3193 AN: 5140

South Asian (SAS) AF: 0.861 AC: 4147 AN: 4816

European-Finnish (FIN) AF: 0.803 AC: 8496 AN: 10576

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55539 AN: 67980

Other (OTH) AF: 0.813 AC: 1713 AN: 2106

Alfa AF: 0.820 Hom.: 10384

Bravo AF: 0.819

Asia WGS AF: 0.747 AC: 2601 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.4
DANN	Benign	0.57
PhyloP100		-0.61
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: rs547954; hg19: chr12-117754506; COSMIC: COSV108164949;