rs478597

Variant names:

• chr12-117313620-G-A
• rs478597
• NM_000620.5:c.726-2028C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-117313620-G-A
• chr12-117313620-G-C
• chr12-117313620-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.726-2028C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,862 control chromosomes in the GnomAD database, including 9,619 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 0.35 (9619 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470
• Publications: 16 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.726-2028C>T		intron_variant	Intron 2 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.726-2028C>T		intron_variant	Intron 2 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.726-2028C>T		intron_variant	Intron 2 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.726-2028C>T		intron_variant	Intron 1 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.726-2028C>T		intron_variant	Intron 2 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52980 AN: 151744 Hom.: 9614 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.349 AC: 52993 AN: 151862 Hom.: 9619 Cov.: 31 AF XY: 0.348 AC XY: 25863 AN XY: 74218

African (AFR) AF: 0.319 AC: 13217 AN: 41426

American (AMR) AF: 0.290 AC: 4422 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1213 AN: 5146

South Asian (SAS) AF: 0.371 AC: 1779 AN: 4792

European-Finnish (FIN) AF: 0.392 AC: 4132 AN: 10532

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25538 AN: 67940

Other (OTH) AF: 0.360 AC: 761 AN: 2112

Alfa AF: 0.347 Hom.: 4232

Bravo AF: 0.339

Asia WGS AF: 0.298 AC: 1036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-0.047
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: rs478597; hg19: chr12-117751425;