rs561712

Variant names:

• chr12-117314264-C-T
• rs561712
• NM_000620.5:c.726-2672G>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.726-2672G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 152,012 control chromosomes in the GnomAD database, including 11,389 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 0.38 (11389 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 20 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.726-2672G>A		intron_variant	Intron 2 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.726-2672G>A		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.726-2672G>A		intron_variant	Intron 2 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.726-2672G>A		intron_variant	Intron 1 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.726-2672G>A		intron_variant	Intron 2 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57743 AN: 151894 Hom.: 11380 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.380 AC: 57777 AN: 152012 Hom.: 11389 Cov.: 32 AF XY: 0.379 AC XY: 28125 AN XY: 74298

African (AFR) AF: 0.424 AC: 17593 AN: 41450

American (AMR) AF: 0.306 AC: 4674 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1380 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1225 AN: 5174

South Asian (SAS) AF: 0.371 AC: 1787 AN: 4820

European-Finnish (FIN) AF: 0.397 AC: 4192 AN: 10568

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

European-Non Finnish (NFE) AF: 0.376 AC: 25557 AN: 67950

Other (OTH) AF: 0.378 AC: 798 AN: 2112

Alfa AF: 0.377 Hom.: 15020

Bravo AF: 0.374

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.69
PhyloP100		-0.052
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: rs561712; hg19: chr12-117752069;