12-117291469-C-T

Variant names:

• chr12-117291469-C-T
• rs7309163
• NM_000620.5:c.853-1043G>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.853-1043G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 150,012 control chromosomes in the GnomAD database, including 13,228 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 0.41 (13228 hom., cov: 27)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.364
• Publications: 15 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.853-1043G>A		intron_variant	Intron 3 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.853-1043G>A		intron_variant	Intron 3 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.-156-1043G>A		intron_variant	Intron 2 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.-156-1043G>A		intron_variant	Intron 2 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.853-1043G>A		intron_variant	Intron 3 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.853-1043G>A		intron_variant	Intron 2 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.853-1043G>A		intron_variant	Intron 3 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 61281 AN: 149920 Hom.: 13207 Cov.: 27

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.409 AC: 61334 AN: 150012 Hom.: 13228 Cov.: 27 AF XY: 0.407 AC XY: 29755 AN XY: 73094

African (AFR) AF: 0.540 AC: 21982 AN: 40694

American (AMR) AF: 0.312 AC: 4705 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1216 AN: 3462

East Asian (EAS) AF: 0.399 AC: 2002 AN: 5020

South Asian (SAS) AF: 0.355 AC: 1689 AN: 4756

European-Finnish (FIN) AF: 0.376 AC: 3753 AN: 9980

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

European-Non Finnish (NFE) AF: 0.363 AC: 24602 AN: 67738

Other (OTH) AF: 0.394 AC: 814 AN: 2068

Alfa AF: 0.380 Hom.: 22812

Bravo AF: 0.412

Asia WGS AF: 0.364 AC: 1265 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.67
PhyloP100		0.36
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: rs7309163; hg19: chr12-117729274;