NM_000603.5:c.1998C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000603.5(NOS3):c.1998C>G(p.Ala666Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,552 control chromosomes in the GnomAD database, including 72,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10911 hom., cov: 33)

Exomes 𝑓: 0.28 ( 61217 hom. )

Consequence

NOS3
NM_000603.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.57

Publications

28 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 7-151007162-C-G is Benign according to our data. Variant chr7-151007162-C-G is described in ClinVar as Benign. ClinVar VariationId is 403249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.1998C>G	p.Ala666Ala	synonymous	Exon 17 of 27	NP_000594.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1998C>G	p.Ala666Ala	synonymous	Exon 17 of 27	ENSP00000297494.3
	NOS3	ENST00000461406.5	TSL:2	c.1380C>G	p.Ala460Ala	synonymous	Exon 14 of 24	ENSP00000417143.1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54276

AN:

151992

Hom.:

10867

Cov.:

show subpopulations

Gnomad AFR

AF:

0.503

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.456

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.345

AC:

86546

AN:

250728

AF XY:

0.330

show subpopulations

Gnomad AFR exome

AF:

0.511

Gnomad AMR exome

AF:

0.587

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.276

AC:

403907

AN:

1461442

Hom.:

61217

Cov.:

AF XY:

0.277

AC XY:

201252

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.510

AC:

17074

AN:

33474

American (AMR)

AF:

0.575

AC:

25723

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

6028

AN:

26126

East Asian (EAS)

AF:

0.409

AC:

16219

AN:

39696

South Asian (SAS)

AF:

0.347

AC:

29934

AN:

86252

European-Finnish (FIN)

AF:

0.343

AC:

18213

AN:

53108

Middle Eastern (MID)

AF:

0.268

AC:

1548

AN:

5768

European-Non Finnish (NFE)

AF:

0.245

AC:

271991

AN:

1111914

Other (OTH)

AF:

0.284

AC:

17177

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

18453

36906

55358

73811

92264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9514

19028

28542

38056

47570

<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:

0.357

AC:

54376

AN:

152110

Hom.:

10911

Cov.:

AF XY:

0.363

AC XY:

26992

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.503

AC:

20872

AN:

41484

American (AMR)

AF:

0.457

AC:

6984

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

829

AN:

3470

East Asian (EAS)

AF:

0.371

AC:

1911

AN:

5156

South Asian (SAS)

AF:

0.364

AC:

1758

AN:

4830

European-Finnish (FIN)

AF:

0.351

AC:

3722

AN:

10598

Middle Eastern (MID)

AF:

0.260

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.255

AC:

17329

AN:

67968

Other (OTH)

AF:

0.335

AC:

708

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1698

3396

5095

6793

8491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<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:

0.233

Hom.:

1346

Bravo

AF:

0.376

Asia WGS

AF:

0.378

AC:

1312

AN:

3478

EpiCase

AF:

0.246

EpiControl

AF:

0.244

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Oct 18, 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).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.1

(source)

DANN

Benign

0.74

PhyloP100

-1.6

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over