12-117236534-C-T

Variant names:

• chr12-117236534-C-T
• rs10774910
• NM_000620.5:c.3042-1776G>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.3042-1776G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,028 control chromosomes in the GnomAD database, including 18,468 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 0.46 (18468 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.224
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3042-1776G>A		intron_variant	Intron 20 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3144-1776G>A		intron_variant	Intron 21 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2034-1776G>A		intron_variant	Intron 19 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2034-1776G>A		intron_variant	Intron 19 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3042-1776G>A		intron_variant	Intron 20 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3144-1776G>A		intron_variant	Intron 20 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3144-1776G>A		intron_variant	Intron 21 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69358 AN: 151910 Hom.: 18410 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.457 AC: 69480 AN: 152028 Hom.: 18468 Cov.: 32 AF XY: 0.456 AC XY: 33853 AN XY: 74298

African (AFR) AF: 0.717 AC: 29743 AN: 41472

American (AMR) AF: 0.547 AC: 8352 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1229 AN: 3470

East Asian (EAS) AF: 0.464 AC: 2392 AN: 5156

South Asian (SAS) AF: 0.423 AC: 2035 AN: 4810

European-Finnish (FIN) AF: 0.234 AC: 2470 AN: 10576

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21841 AN: 67962

Other (OTH) AF: 0.449 AC: 948 AN: 2110

Alfa AF: 0.361 Hom.: 5658

Bravo AF: 0.492

Asia WGS AF: 0.508 AC: 1767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.1
DANN	Benign	0.64
PhyloP100		0.22
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: rs10774910; hg19: chr12-117674339;