chr12-117282380-C-A

Variant names:

• chr12-117282380-C-A
• rs3825102
• NM_000620.5:c.1383-1514G>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.1383-1514G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,028 control chromosomes in the GnomAD database, including 7,659 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 0.30 (7659 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 14 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1383-1514G>T		intron_variant	Intron 7 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1383-1514G>T		intron_variant	Intron 7 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.375-1514G>T		intron_variant	Intron 6 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.375-1514G>T		intron_variant	Intron 6 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1383-1514G>T		intron_variant	Intron 7 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1383-1514G>T		intron_variant	Intron 6 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1383-1514G>T		intron_variant	Intron 7 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46271 AN: 151910 Hom.: 7658 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.304 AC: 46281 AN: 152028 Hom.: 7659 Cov.: 32 AF XY: 0.306 AC XY: 22742 AN XY: 74328

African (AFR) AF: 0.196 AC: 8139 AN: 41482

American (AMR) AF: 0.266 AC: 4070 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1348 AN: 5166

South Asian (SAS) AF: 0.344 AC: 1653 AN: 4812

European-Finnish (FIN) AF: 0.384 AC: 4058 AN: 10556

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24537 AN: 67948

Other (OTH) AF: 0.317 AC: 671 AN: 2114

Alfa AF: 0.343 Hom.: 39784

Bravo AF: 0.291

Asia WGS AF: 0.278 AC: 965 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		0.33
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: rs3825102; hg19: chr12-117720185;