chr12-117236324-C-G

Variant names:

• chr12-117236324-C-G
• rs10774909
• NM_000620.5:c.3042-1566G>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.3042-1566G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 151,906 control chromosomes in the GnomAD database, including 7,037 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 0.28 (7037 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.313
• Publications: 13 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3042-1566G>C		intron_variant	Intron 20 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3144-1566G>C		intron_variant	Intron 21 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2034-1566G>C		intron_variant	Intron 19 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2034-1566G>C		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.3042-1566G>C		intron_variant	Intron 20 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3144-1566G>C		intron_variant	Intron 20 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3144-1566G>C		intron_variant	Intron 21 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42711 AN: 151788 Hom.: 7006 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.282 AC: 42795 AN: 151906 Hom.: 7037 Cov.: 32 AF XY: 0.280 AC XY: 20812 AN XY: 74226

African (AFR) AF: 0.450 AC: 18653 AN: 41406

American (AMR) AF: 0.231 AC: 3530 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1986 AN: 5164

South Asian (SAS) AF: 0.238 AC: 1141 AN: 4794

European-Finnish (FIN) AF: 0.155 AC: 1630 AN: 10548

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13965 AN: 67940

Other (OTH) AF: 0.284 AC: 599 AN: 2110

Alfa AF: 0.249 Hom.: 673

Bravo AF: 0.293

Asia WGS AF: 0.372 AC: 1293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.31
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: rs10774909; hg19: chr12-117674129;