12-117350435-C-T

Variant names:

• chr12-117350435-C-T
• rs3782219
• NM_000620.5:c.-421+11077G>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.-421+11077G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,128 control chromosomes in the GnomAD database, including 2,795 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 0.17 (2795 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 10 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.-421+11077G>A		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.-421+11077G>A		intron	N/A	NP_001191147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-421+11077G>A		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000618760.4	TSL:5	c.-421+11077G>A		intron	N/A	ENSP00000477999.1
	NOS1	ENST00000477584.1	TSL:2	n.119-2043G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26246 AN: 152008 Hom.: 2796 Cov.: 32

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.172 AC: 26239 AN: 152128 Hom.: 2795 Cov.: 32 AF XY: 0.177 AC XY: 13181 AN XY: 74362

African (AFR) AF: 0.0586 AC: 2435 AN: 41528

American (AMR) AF: 0.190 AC: 2911 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.388 AC: 1995 AN: 5148

South Asian (SAS) AF: 0.127 AC: 613 AN: 4826

European-Finnish (FIN) AF: 0.272 AC: 2872 AN: 10568

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14232 AN: 67986

Other (OTH) AF: 0.174 AC: 367 AN: 2106

Alfa AF: 0.179 Hom.: 602

Bravo AF: 0.162

Asia WGS AF: 0.229 AC: 794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.6
DANN	Benign	0.78
PhyloP100		0.0070
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: rs3782219; hg19: chr12-117788240;