7-150999023-T-G

Position:

chr7-150999023-T-G

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:3O:5

Conservation

PhyloP100: -0.502

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 made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE
NOS3	NM_000603.5 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	8/27	ENST00000297494.8
NOS3	NM_001160111.1 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	7/14
NOS3	NM_001160110.1 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	7/14
NOS3	NM_001160109.2 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	8/27	1	NM_000603.5	P1	P29474-1
NOS3	ENST00000484524.5 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	7/14	1			P29474-2
NOS3	ENST00000467517.1 linkuse as main transcript	c.894T>G	p.Asp298Glu	missense_variant	7/14	1			P29474-3
NOS3	ENST00000461406.5 linkuse as main transcript	c.276T>G	p.Asp92Glu	missense_variant	5/24	2

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

GnomAD3 exomes

AF:

0.751

AC:

187223

AN:

249394

Hom.:

71390

AF XY:

0.745

AC XY:

100872

AN XY:

135440

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 SAS exome

AF:

0.820

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

Gnomad4 AFR exome

AF:

0.892

Gnomad4 AMR exome

AF:

0.809

Gnomad4 ASJ exome

AF:

0.791

Gnomad4 EAS exome

AF:

0.906

Gnomad4 SAS exome

AF:

0.815

Gnomad4 FIN exome

AF:

0.714

Gnomad4 NFE exome

AF:

0.662

Gnomad4 OTH exome

AF:

0.717

GnomAD4 genome

AF:

0.756

AC:

114817

AN:

151958

Hom.:

44214

Cov.:

AF XY:

0.758

AC XY:

56247

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.886

Gnomad4 AMR

AF:

0.744

Gnomad4 ASJ

AF:

0.807

Gnomad4 EAS

AF:

0.888

Gnomad4 SAS

AF:

0.821

Gnomad4 FIN

AF:

0.706

Gnomad4 NFE

AF:

0.669

Gnomad4 OTH

AF:

0.747

Alfa

AF:

0.703

Hom.:

13899

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:3Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertension resistant to conventional therapy

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

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) -

Ischemic stroke

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Alzheimer disease, late-onset, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Ischemic heart disease, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Hypertension, pregnancy-induced, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Coronary artery spasm 1, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

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

DANN

Benign

0.22

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

MutationTaster

Benign

1.0

P;P;P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over