12-117324894-C-G

Variant names:

• chr12-117324894-C-G
• rs816293
• NM_000620.5:c.725+5451G>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.725+5451G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,006 control chromosomes in the GnomAD database, including 11,490 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 0.38 (11490 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.725+5451G>C		intron_variant	Intron 2 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.725+5451G>C		intron_variant	Intron 2 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.725+5451G>C		intron_variant	Intron 2 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.725+5451G>C		intron_variant	Intron 1 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.725+5451G>C		intron_variant	Intron 2 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58406 AN: 151888 Hom.: 11481 Cov.: 32

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.384 AC: 58441 AN: 152006 Hom.: 11490 Cov.: 32 AF XY: 0.384 AC XY: 28546 AN XY: 74288

African (AFR) AF: 0.403 AC: 16691 AN: 41456

American (AMR) AF: 0.320 AC: 4885 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1576 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1404 AN: 5150

South Asian (SAS) AF: 0.399 AC: 1924 AN: 4818

European-Finnish (FIN) AF: 0.394 AC: 4154 AN: 10550

Middle Eastern (MID) AF: 0.476 AC: 138 AN: 290

European-Non Finnish (NFE) AF: 0.388 AC: 26382 AN: 67980

Other (OTH) AF: 0.393 AC: 829 AN: 2110

Alfa AF: 0.394 Hom.: 1484

Bravo AF: 0.378

Asia WGS AF: 0.334 AC: 1161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.073
DANN	Benign	0.52
PhyloP100		-2.5
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: rs816293; hg19: chr12-117762699; COSMIC: COSV108164951;