12-117323735-A-G

Variant names:

• chr12-117323735-A-G
• rs1483757
• NM_000620.5:c.725+6610T>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.725+6610T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 151,896 control chromosomes in the GnomAD database, including 14,010 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 0.43 (14010 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461
• Publications: 22 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.504 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.725+6610T>C		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.725+6610T>C		intron	N/A	NP_001191147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.725+6610T>C		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.725+6610T>C		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.725+6610T>C		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64528 AN: 151778 Hom.: 14003 Cov.: 31

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.424

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

GnomAD4 genome AF: 0.425 AC: 64571 AN: 151896 Hom.: 14010 Cov.: 31 AF XY: 0.425 AC XY: 31537 AN XY: 74226

African (AFR) AF: 0.355 AC: 14701 AN: 41428

American (AMR) AF: 0.513 AC: 7830 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2472 AN: 5150

South Asian (SAS) AF: 0.458 AC: 2205 AN: 4810

European-Finnish (FIN) AF: 0.410 AC: 4324 AN: 10556

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.444 AC: 30145 AN: 67914

Other (OTH) AF: 0.422 AC: 891 AN: 2110

Alfa AF: 0.436 Hom.: 34972

Bravo AF: 0.431

Asia WGS AF: 0.440 AC: 1534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.087
DANN	Benign	0.42
PhyloP100		-0.46
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: rs1483757; hg19: chr12-117761540;