12-117335030-A-G

Variant names:

• chr12-117335030-A-G
• rs576881
• NM_000620.5:c.-420-3541T>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.-420-3541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,002 control chromosomes in the GnomAD database, including 9,602 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 (9602 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-420-3541T>C		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-420-3541T>C		intron_variant	Intron 1 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.-420-3541T>C		intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000618760.4	c.-420-3541T>C		intron_variant	Intron 1 of 29	5		ENSP00000477999.1
NOS1	ENST00000549189.1	n.471-3541T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53141 AN: 151884 Hom.: 9594 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.371

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

GnomAD4 genome AF: 0.350 AC: 53170 AN: 152002 Hom.: 9602 Cov.: 32 AF XY: 0.347 AC XY: 25757 AN XY: 74298

African (AFR) AF: 0.318 AC: 13165 AN: 41432

American (AMR) AF: 0.301 AC: 4585 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1529 AN: 3466

East Asian (EAS) AF: 0.226 AC: 1171 AN: 5174

South Asian (SAS) AF: 0.338 AC: 1629 AN: 4822

European-Finnish (FIN) AF: 0.360 AC: 3804 AN: 10564

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25844 AN: 67978

Other (OTH) AF: 0.367 AC: 773 AN: 2108

Alfa AF: 0.369 Hom.: 31997

Bravo AF: 0.343

Asia WGS AF: 0.294 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.26
PhyloP100		0.094
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs576881; hg19: chr12-117772835;