Variant rs3918232 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000603.5(NOS3):c.2479G>A(p.Val827Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,543,576 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0046 ( 17 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.51

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065574944).

BP6

Variant 7-151009552-G-A is Benign according to our data. Variant chr7-151009552-G-A is described in ClinVar as [Benign]. Clinvar id is 2658167.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 503 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS3	NM_000603.5 linkuse as main transcript	c.2479G>A	p.Val827Met	missense_variant	20/27	ENST00000297494.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.2479G>A	p.Val827Met	missense_variant	20/27	1	NM_000603.5	P1	P29474-1
NOS3	ENST00000461406.5 linkuse as main transcript	c.1861G>A	p.Val621Met	missense_variant	17/24	2
NOS3	ENST00000475017.1 linkuse as main transcript	c.361G>A	p.Val121Met	missense_variant	3/7	2
NOS3	ENST00000473057.1 linkuse as main transcript	n.423G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00263

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00313

AC:

440

AN:

140414

Hom.:

AF XY:

0.00299

AC XY:

226

AN XY:

75692

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00417

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00458

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00456

AC:

6350

AN:

1391310

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

3153

AN XY:

685926

show subpopulations

Gnomad4 AFR exome

AF:

0.000604

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.000400

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00428

Gnomad4 FIN exome

AF:

0.00168

Gnomad4 NFE exome

AF:

0.00517

Gnomad4 OTH exome

AF:

0.00388

GnomAD4 genome

AF:

0.00330

AC:

503

AN:

152266

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00263

Gnomad4 NFE

AF:

0.00509

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00370

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00141

AC:

103

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

NOS3: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.25

Sift

Benign

0.050

D;T

Sift4G

Uncertain

0.033

D;D

Polyphen

0.48

P;B

Vest4

0.20

MVP

0.74

MPC

0.91

ClinPred

0.032

GERP RS

-0.10

Varity_R

0.13

gMVP

0.37

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

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