chr12-117346913-G-A

Variant names:

• chr12-117346913-G-A
• rs693534
• NM_000620.5:c.-421+14599C>T

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+14599C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,026 control chromosomes in the GnomAD database, including 10,353 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 0.36 (10353 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• Publications: 24 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.-421+14599C>T		intron	N/A	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.-421+14599C>T		intron	N/A	NP_001191147.1	P29475-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-421+14599C>T		intron	N/A	ENSP00000320758.6	P29475-1
	NOS1	ENST00000618760.4	TSL:5	c.-421+14599C>T		intron	N/A	ENSP00000477999.1	P29475-5
	NOS1	ENST00000549189.1	TSL:3	n.471-15424C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55429 AN: 151910 Hom.: 10337 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.365 AC: 55489 AN: 152026 Hom.: 10353 Cov.: 33 AF XY: 0.365 AC XY: 27089 AN XY: 74302

African (AFR) AF: 0.327 AC: 13566 AN: 41458

American (AMR) AF: 0.401 AC: 6129 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1459 AN: 3470

East Asian (EAS) AF: 0.285 AC: 1475 AN: 5168

South Asian (SAS) AF: 0.413 AC: 1987 AN: 4816

European-Finnish (FIN) AF: 0.352 AC: 3717 AN: 10548

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25657 AN: 67986

Other (OTH) AF: 0.392 AC: 827 AN: 2110

Alfa AF: 0.375 Hom.: 7726

Bravo AF: 0.365

Asia WGS AF: 0.348 AC: 1211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.66
PhyloP100		0.49
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: rs693534; hg19: chr12-117784718;