NM_000603.5:c.2654G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000603.5(NOS3):c.2654G>T(p.Arg885Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,000 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 34 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 21 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.02

Publications

20 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=0.003750503).

BP6

Variant 7-151010256-G-T is Benign according to our data. Variant chr7-151010256-G-T is described in ClinVar as [Benign]. Clinvar id is 792094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1548/152362) while in subpopulation AFR AF = 0.035 (1456/41578). AF 95% confidence interval is 0.0335. There are 34 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 1548 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.2654G>T	p.Arg885Met	missense_variant	Exon 21 of 27	ENST00000297494.8	NP_000594.2	P29474-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.2654G>T	p.Arg885Met	missense_variant	Exon 21 of 27	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000461406.5 link	c.2036G>T	p.Arg679Met	missense_variant	Exon 18 of 24	2		ENSP00000417143.1	E7ESA7
NOS3	ENST00000475017.1 link	c.533G>T	p.Arg178Met	missense_variant	Exon 4 of 7	2		ENSP00000418245.1	H7C4V4

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1537

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00296

AC:

739

AN:

249946

AF XY:

0.00228

show subpopulations

Gnomad AFR exome

AF:

0.0359

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00360

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000346

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00127

AC:

1851

AN:

1460638

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

814

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.0374

AC:

1252

AN:

33454

American (AMR)

AF:

0.00190

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00283

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53080

Middle Eastern (MID)

AF:

0.00595

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.000181

AC:

201

AN:

1111872

Other (OTH)

AF:

0.00320

AC:

193

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0102

AC:

1548

AN:

152362

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

740

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0350

AC:

1456

AN:

41578

American (AMR)

AF:

0.00300

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68030

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00355

Hom.:

Bravo

AF:

0.0120

ESP6500AA

AF:

0.0345

AC:

152

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00361

AC:

438

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.10

Sift

Benign

0.12

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0020

B;B

Vest4

0.22

MVP

0.74

MPC

0.74

ClinPred

0.048

GERP RS

4.4

Varity_R

0.077

gMVP

0.34

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -44

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