chr7-150996468-G-A

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.335G>A(p.Arg112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,590,136 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 45 hom., cov: 26)

Exomes 𝑓: 0.0018 ( 42 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.275

Publications

18 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=0.0025461912).

BP6

Variant 7-150996468-G-A is Benign according to our data. Variant chr7-150996468-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182440.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 = 0.0144 (2101/146008) while in subpopulation AFR AF = 0.0499 (1945/38956). AF 95% confidence interval is 0.0481. There are 45 homozygotes in GnomAd4. There are 1011 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 2101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 4 of 27	ENST00000297494.8	NP_000594.2	P29474-1
NOS3	NM_001160111.1 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 3 of 14		NP_001153583.1	P29474-2
NOS3	NM_001160110.1 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 3 of 14		NP_001153582.1	P29474-3
NOS3	NM_001160109.2 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 3 of 14		NP_001153581.1	P29474A0S0A6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 4 of 27	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 3 of 14	1		ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1 link	c.335G>A	p.Arg112Gln	missense_variant	Exon 3 of 14	1		ENSP00000420551.1	P29474-3
NOS3	ENST00000461406.5 link	c.-37+1154G>A		intron_variant	Intron 2 of 23	2		ENSP00000417143.1	E7ESA7

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2100

AN:

145902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00698

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.000621

Gnomad SAS

AF:

0.000901

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000376

Gnomad OTH

AF:

0.0106

GnomAD2 exomes

AF:

0.00391

AC:

848

AN:

216676

AF XY:

0.00309

show subpopulations

Gnomad AFR exome

AF:

0.0541

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.000215

Gnomad EAS exome

AF:

0.0000600

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000554

Gnomad OTH exome

AF:

0.00258

GnomAD4 exome

AF:

0.00177

AC:

2559

AN:

1444128

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1120

AN XY:

716674

show subpopulations

African (AFR)

AF:

0.0516

AC:

1710

AN:

33170

American (AMR)

AF:

0.00363

AC:

154

AN:

42408

Ashkenazi Jewish (ASJ)

AF:

0.000117

AC:

AN:

25726

East Asian (EAS)

AF:

0.00125

AC:

AN:

39120

South Asian (SAS)

AF:

0.000167

AC:

AN:

83960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50640

Middle Eastern (MID)

AF:

0.00453

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000354

AC:

391

AN:

1103626

Other (OTH)

AF:

0.00355

AC:

212

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

126

253

379

506

632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0144

AC:

2101

AN:

146008

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1011

AN XY:

70890

show subpopulations

African (AFR)

AF:

0.0499

AC:

1945

AN:

38956

American (AMR)

AF:

0.00697

AC:

102

AN:

14628

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3428

East Asian (EAS)

AF:

0.000623

AC:

AN:

4816

South Asian (SAS)

AF:

0.000677

AC:

AN:

4432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000376

AC:

AN:

66566

Other (OTH)

AF:

0.0105

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

170

254

339

424

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:

0.00626

Hom.:

Bravo

AF:

0.0173

ESP6500AA

AF:

0.0449

AC:

194

ESP6500EA

AF:

0.000586

AC:

ExAC

AF:

0.00454

AC:

543

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

NOS3-related disorder

Benign:1

May 14, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

0.28

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.94

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.57

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.79

P;.;.

Vest4

0.12

MVP

0.49

MPC

0.073

ClinPred

0.0075

GERP RS

3.9

Varity_R

0.080

gMVP

0.43

Mutation Taster

=99/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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