7-150999023-T-G

Variant names:

Variant summary

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

The NM_000603.5(NOS3):c.894T>G(p.Asp298Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 1,612,084 control chromosomes in the GnomAD database, including 399,768 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44214 hom., cov: 30)

Exomes 𝑓: 0.69 ( 355554 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5O:5

Conservation

PhyloP100: -0.502

Publications

1918 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=8.4196944E-7).

BP6

Variant 7-150999023-T-G is Benign according to our data. Variant chr7-150999023-T-G is described in ClinVar as Benign. ClinVar VariationId is 14015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NOS3	NM_000603.5 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 8 of 27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 7 of 14		NP_001153583.1
NOS3	NM_001160110.1 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 7 of 14		NP_001153582.1
NOS3	NM_001160109.2 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 7 of 14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NOS3	ENST00000297494.8 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 8 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 7 of 14	1		ENSP00000420215.1
NOS3	ENST00000467517.1 link	c.894T>G	p.Asp298Glu	missense_variant	Exon 7 of 14	1		ENSP00000420551.1
NOS3	ENST00000461406.5 link	c.276T>G	p.Asp92Glu	missense_variant	Exon 5 of 24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes

AF:

0.755

AC:

114696

AN:

151842

Hom.:

44151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.767

Gnomad AMR

AF:

0.744

Gnomad ASJ

AF:

0.807

Gnomad EAS

AF:

0.888

Gnomad SAS

AF:

0.820

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.669

Gnomad OTH

AF:

0.745

GnomAD2 exomes

AF:

0.751

AC:

187223

AN:

249394

AF XY:

0.745

show subpopulations

Gnomad AFR exome

AF:

0.891

Gnomad AMR exome

AF:

0.816

Gnomad ASJ exome

AF:

0.791

Gnomad EAS exome

AF:

0.892

Gnomad FIN exome

AF:

0.707

Gnomad NFE exome

AF:

0.675

Gnomad OTH exome

AF:

0.721

GnomAD4 exome

AF:

0.694

AC:

1013298

AN:

1460126

Hom.:

355554

Cov.:

AF XY:

0.697

AC XY:

506539

AN XY:

726378

show subpopulations

African (AFR)

AF:

0.892

AC:

29851

AN:

33464

American (AMR)

AF:

0.809

AC:

36132

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.791

AC:

20672

AN:

26120

East Asian (EAS)

AF:

0.906

AC:

35962

AN:

39698

South Asian (SAS)

AF:

0.815

AC:

70283

AN:

86234

European-Finnish (FIN)

AF:

0.714

AC:

37192

AN:

52072

Middle Eastern (MID)

AF:

0.746

AC:

4301

AN:

5766

European-Non Finnish (NFE)

AF:

0.662

AC:

735651

AN:

1111776

Other (OTH)

AF:

0.717

AC:

43254

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

18406

36812

55217

73623

92029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19284

38568

57852

77136

96420

<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:

0.756

AC:

114817

AN:

151958

Hom.:

44214

Cov.:

AF XY:

0.758

AC XY:

56247

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.886

AC:

36756

AN:

41472

American (AMR)

AF:

0.744

AC:

11366

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.807

AC:

2794

AN:

3464

East Asian (EAS)

AF:

0.888

AC:

4556

AN:

5132

South Asian (SAS)

AF:

0.821

AC:

3953

AN:

4816

European-Finnish (FIN)

AF:

0.706

AC:

7453

AN:

10562

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.669

AC:

45448

AN:

67922

Other (OTH)

AF:

0.747

AC:

1576

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1387

2774

4160

5547

6934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.715

Hom.:

21119

Bravo

AF:

0.765

TwinsUK

AF:

0.657

AC:

2438

ALSPAC

AF:

0.648

AC:

2498

ESP6500AA

AF:

0.884

AC:

3897

ESP6500EA

AF:

0.676

AC:

5803

ExAC

AF:

0.751

AC:

90786

Asia WGS

AF:

0.850

AC:

2954

AN:

3478

EpiCase

AF:

0.663

EpiControl

AF:

0.662

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:5Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ischemic stroke;C1863052:Alzheimer disease type 1;C5574918:Preeclampsia/eclampsia 1;CN305331:Essential hypertension, genetic

Benign:2

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19435423, 21706163, 25095657, 20467051, 20854685, 19364839, 19158254, 21607713, 19560472, 17919260, 25937798, 20083095, 21816783, 17449720, 22025889, 19531501, 21919778, 21320716, 22561696, 21406182, 19929133, 19373110, 20691505, 23342892, 11823442, 23922896, 19804474, 20103956, 18815450, 18629615, 19087148, 20367485, 20193212, 22940147, 20049477, 23594558, 19773668, 9737779, 10451235, 11354626) -

HYPERTENSION RESISTANT TO CONVENTIONAL THERAPY

Pathogenic:1

Apr 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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, variant associated with coronary artery spasm, alzheimers, hypertension, stroke, heart disease -

HYPERTENSION, PREGNANCY-INDUCED, SUSCEPTIBILITY TO

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Alzheimer disease, late-onset, susceptibility to

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Ischemic stroke

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

CORONARY ARTERY SPASM 1, SUSCEPTIBILITY TO

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ISCHEMIC HEART DISEASE, SUSCEPTIBILITY TO

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.8

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0056

.;T;.;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.18

T;T;T;T

MetaRNN

Benign

8.4e-7

T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-0.50

PrimateAI

Benign

0.43

PROVEAN

Benign

0.90

N;N;N;N

REVEL

Benign

0.057

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.048

MutPred

0.43

.;Loss of sheet (P = 0.0817);.;.;

MPC

0.061

ClinPred

0.00013

GERP RS

1.0

Varity_R

0.013

gMVP

0.53

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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