rs3741475

Positions:

• chr12-117232109-G-A

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.3258C>T​(p.Asp1086=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,611,444 control chromosomes in the GnomAD database, including 36,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4120 hom., cov: 31)
  • Exomes 𝑓: 0.21 (32851 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.259

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=-0.59).
• BP6: Variant 12-117232109-G-A is Benign according to our data. Variant chr12-117232109-G-A is described in ClinVar as [Benign]. Clinvar id is 3061017.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3258C>T	p.Asp1086=	synonymous_variant	22/29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3360C>T	p.Asp1120=	synonymous_variant	23/30		NP_001191147.1
NOS1	NM_001204213.2	c.2250C>T	p.Asp750=	synonymous_variant	21/28		NP_001191142.1
NOS1	NM_001204214.2	c.2250C>T	p.Asp750=	synonymous_variant	21/28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3258C>T	p.Asp1086=	synonymous_variant	22/29	1	NM_000620.5	ENSP00000320758	P1
NOS1	ENST00000338101.8	c.3360C>T	p.Asp1120=	synonymous_variant	22/29	5		ENSP00000337459
NOS1	ENST00000618760.4	c.3360C>T	p.Asp1120=	synonymous_variant	23/30	5		ENSP00000477999

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34391 AN: 151852 Hom.: 4106 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.220 AC: 54746 AN: 248876 Hom.: 6324 AF XY: 0.222 AC XY: 30035 AN XY: 135030

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.330

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.209 AC: 304892 AN: 1459474 Hom.: 32851 Cov.: 33 AF XY: 0.211 AC XY: 153112 AN XY: 726056

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.227 AC: 34436 AN: 151970 Hom.: 4120 Cov.: 31 AF XY: 0.227 AC XY: 16856 AN XY: 74294

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.253

Alfa AF: 0.216 Hom.: 5969

Bravo AF: 0.230

Asia WGS AF: 0.325 AC: 1129 AN: 3478

EpiCase AF: 0.223

EpiControl AF: 0.226

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 17, 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	-0.59
CADD	Benign	0.73
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs3741475; hg19: chr12-117669914; COSMIC: COSV57608414;