chr12-117247333-T-C

Variant names:

• chr12-117247333-T-C
• rs2291908
• NM_000620.5:c.2823+15A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.2823+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,555,138 control chromosomes in the GnomAD database, including 80,006 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 (7571 hom., cov: 30)
  • Exomes 𝑓: 0.32 (72435 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 16 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2823+15A>G		intron_variant	Intron 18 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2925+15A>G		intron_variant	Intron 19 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1815+15A>G		intron_variant	Intron 17 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1815+15A>G		intron_variant	Intron 17 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2823+15A>G		intron_variant	Intron 18 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2925+15A>G		intron_variant	Intron 18 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2925+15A>G		intron_variant	Intron 19 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45050 AN: 151422 Hom.: 7548 Cov.: 30

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.345 AC: 76325 AN: 221082 AF XY: 0.338

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.316 AC: 443596 AN: 1403598 Hom.: 72435 Cov.: 29 AF XY: 0.316 AC XY: 219902 AN XY: 696132

African (AFR) AF: 0.194 AC: 6103 AN: 31378

American (AMR) AF: 0.580 AC: 22122 AN: 38128

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8010 AN: 23942

East Asian (EAS) AF: 0.487 AC: 18489 AN: 37976

South Asian (SAS) AF: 0.329 AC: 26398 AN: 80176

European-Finnish (FIN) AF: 0.255 AC: 13357 AN: 52392

Middle Eastern (MID) AF: 0.332 AC: 1834 AN: 5522

European-Non Finnish (NFE) AF: 0.305 AC: 327907 AN: 1076040

Other (OTH) AF: 0.334 AC: 19376 AN: 58044

GnomAD4 genome AF: 0.298 AC: 45095 AN: 151540 Hom.: 7571 Cov.: 30 AF XY: 0.301 AC XY: 22301 AN XY: 74036

African (AFR) AF: 0.197 AC: 8158 AN: 41336

American (AMR) AF: 0.485 AC: 7372 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1190 AN: 3470

East Asian (EAS) AF: 0.501 AC: 2571 AN: 5132

South Asian (SAS) AF: 0.321 AC: 1534 AN: 4778

European-Finnish (FIN) AF: 0.237 AC: 2484 AN: 10494

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20656 AN: 67832

Other (OTH) AF: 0.340 AC: 712 AN: 2096

Alfa AF: 0.309 Hom.: 27291

Bravo AF: 0.312

Asia WGS AF: 0.416 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.77
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2291908; hg19: chr12-117685138; COSMIC: COSV57613555; COSMIC: COSV57613555;