rs79467411

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000484524.5(NOS3):c.1805G>A(p.Cys602Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0958 in 452,870 control chromosomes in the GnomAD database, including 2,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 900 hom., cov: 32)

Exomes 𝑓: 0.093 ( 1519 hom. )

Consequence

NOS3
ENST00000484524.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.911

Publications

2 publications found

Variant links:

Genes affected

NOS3 (HGNC:7876): (nitric oxide synthase 3) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

NOS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013646781).

BP6

Variant 7-151003203-G-A is Benign according to our data. Variant chr7-151003203-G-A is described in ClinVar as Benign. ClinVar VariationId is 403247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NOS3	NM_000603.5 link	c.1752+899G>A		intron_variant	Intron 14 of 26	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1 link	c.1805G>A	p.Cys602Tyr	missense_variant	Exon 14 of 14		NP_001153583.1
NOS3	NM_001160110.1 link	c.1753-108G>A		intron_variant	Intron 13 of 13		NP_001153582.1
NOS3	NM_001160109.2 link	c.1753-454G>A		intron_variant	Intron 13 of 13		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8 link	c.1752+899G>A		intron_variant	Intron 14 of 26	1	NM_000603.5	ENSP00000297494.3

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15467

AN:

151964

Hom.:

902

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0767

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0881

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0792

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0915

AC:

11649

AN:

127250

AF XY:

0.0956

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.0595

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.0872

Gnomad FIN exome

AF:

0.0946

Gnomad NFE exome

AF:

0.0757

Gnomad OTH exome

AF:

0.0824

GnomAD4 exome

AF:

0.0928

AC:

27920

AN:

300788

Hom.:

1519

Cov.:

AF XY:

0.0988

AC XY:

16928

AN XY:

171310

show subpopulations

African (AFR)

AF:

0.148

AC:

1263

AN:

8548

American (AMR)

AF:

0.0597

AC:

1620

AN:

27118

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

1090

AN:

10754

East Asian (EAS)

AF:

0.0915

AC:

840

AN:

9176

South Asian (SAS)

AF:

0.138

AC:

8214

AN:

59398

European-Finnish (FIN)

AF:

0.0934

AC:

1154

AN:

12352

Middle Eastern (MID)

AF:

0.108

AC:

124

AN:

1146

European-Non Finnish (NFE)

AF:

0.0785

AC:

12429

AN:

158310

Other (OTH)

AF:

0.0848

AC:

1186

AN:

13986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1326

2651

3977

5302

6628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15463

AN:

152082

Hom.:

900

Cov.:

AF XY:

0.103

AC XY:

7681

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.146

AC:

6066

AN:

41458

American (AMR)

AF:

0.0765

AC:

1169

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

353

AN:

3472

East Asian (EAS)

AF:

0.0881

AC:

456

AN:

5174

South Asian (SAS)

AF:

0.142

AC:

685

AN:

4814

European-Finnish (FIN)

AF:

0.101

AC:

1065

AN:

10580

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0792

AC:

5387

AN:

67990

Other (OTH)

AF:

0.107

AC:

226

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

675

1349

2024

2698

3373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0941

Hom.:

127

Bravo

AF:

0.100

TwinsUK

AF:

0.0666

AC:

247

ALSPAC

AF:

0.0675

AC:

260

ExAC

AF:

0.0994

AC:

1437

Asia WGS

AF:

0.124

AC:

431

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

NOS3-related disorder

Benign:1

Dec 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.6

(source)

DANN

Benign

0.31

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0031

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

PhyloP100

-0.91

PROVEAN

Benign

2.1

REVEL

Benign

0.048

Sift

Benign

0.12

Sift4G

Benign

0.12

Vest4

0.051

ClinPred

0.0015

GERP RS

-0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over