12-117247465-G-A

Variant names:

• chr12-117247465-G-A
• rs1047735
• NM_000620.5:c.2706C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000620.5(NOS1):​c.2706C>T​(p.His902His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,611,784 control chromosomes in the GnomAD database, including 82,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.30 (7477 hom., cov: 30)
  • Exomes 𝑓: 0.31 (74825 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.37

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-117247465-G-A is Benign according to our data. Variant chr12-117247465-G-A is described in ClinVar as [Benign]. Clinvar id is 3060800.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2706C>T	p.His902His	synonymous_variant	Exon 18 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2808C>T	p.His936His	synonymous_variant	Exon 19 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.1698C>T	p.His566His	synonymous_variant	Exon 17 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.1698C>T	p.His566His	synonymous_variant	Exon 17 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2706C>T	p.His902His	synonymous_variant	Exon 18 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2808C>T	p.His936His	synonymous_variant	Exon 18 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2808C>T	p.His936His	synonymous_variant	Exon 19 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44776 AN: 151302 Hom.: 7453 Cov.: 30

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.329

GnomAD3 exomes AF: 0.350 AC: 86657 AN: 247758 Hom.: 17160 AF XY: 0.341 AC XY: 45811 AN XY: 134432

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.493

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.313 AC: 457509 AN: 1460364 Hom.: 74825 Cov.: 35 AF XY: 0.313 AC XY: 227195 AN XY: 726476

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.587

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.482

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.296 AC: 44823 AN: 151420 Hom.: 7477 Cov.: 30 AF XY: 0.299 AC XY: 22117 AN XY: 73932

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.337

Alfa AF: 0.310 Hom.: 9872

Bravo AF: 0.311

Asia WGS AF: 0.407 AC: 1415 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.307

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

Oct 18, 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	-0.76
CADD	Benign	0.017
DANN	Benign	0.87

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: rs1047735; hg19: chr12-117685270; COSMIC: COSV57613564; COSMIC: COSV57613564;