rs9658446

Positions:

• chr12-117253685-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000620.5(NOS1):​c.2601C>T​(p.Pro867Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00904 in 1,613,904 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (134 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (186 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.52

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-117253685-G-A is Benign according to our data. Variant chr12-117253685-G-A is described in ClinVar as [Benign]. Clinvar id is 3055936.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2601C>T	p.Pro867Pro	synonymous_variant	17/29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2703C>T	p.Pro901Pro	synonymous_variant	18/30		NP_001191147.1
NOS1	NM_001204213.2	c.1593C>T	p.Pro531Pro	synonymous_variant	16/28		NP_001191142.1
NOS1	NM_001204214.2	c.1593C>T	p.Pro531Pro	synonymous_variant	16/28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2601C>T	p.Pro867Pro	synonymous_variant	17/29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2703C>T	p.Pro901Pro	synonymous_variant	17/29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2703C>T	p.Pro901Pro	synonymous_variant	18/30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3935 AN: 151996 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0202

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0122 AC: 3034 AN: 249510 Hom.: 78 AF XY: 0.0118 AC XY: 1601 AN XY: 135352

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00728 AC: 10642 AN: 1461790 Hom.: 186 Cov.: 30 AF XY: 0.00756 AC XY: 5499 AN XY: 727216

Gnomad4 AFR exome AF: 0.0798

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00394

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0259 AC: 3941 AN: 152114 Hom.: 134 Cov.: 32 AF XY: 0.0253 AC XY: 1881 AN XY: 74370

Gnomad4 AFR AF: 0.0788

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0202

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0140 Hom.: 43

Bravo AF: 0.0294

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NOS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.0
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs9658446; hg19: chr12-117691490;