Genetic Variant NOS3:p.Arg40Gly (chr7-150993921-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000603.5(NOS3):c.118C>G(p.Arg40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.434

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06047198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	NM_000603.5	MANE Select	c.118C>G	p.Arg40Gly	missense	Exon 2 of 27	NP_000594.2
NOS3	NM_001160111.1		c.118C>G	p.Arg40Gly	missense	Exon 1 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.118C>G	p.Arg40Gly	missense	Exon 1 of 14	NP_001153582.1	P29474-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.118C>G	p.Arg40Gly	missense	Exon 2 of 27	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.118C>G	p.Arg40Gly	missense	Exon 1 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.118C>G	p.Arg40Gly	missense	Exon 1 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

185948

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1428664

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32696

American (AMR)

AF:

0.00

AC:

AN:

40072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25536

East Asian (EAS)

AF:

0.00

AC:

AN:

37806

South Asian (SAS)

AF:

0.00

AC:

AN:

82610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4816

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1097300

Other (OTH)

AF:

0.00

AC:

AN:

59022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000865

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.9

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.12

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.80

M_CAP

Benign

0.0079

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.43

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.11

REVEL

Benign

0.054

Sift

Benign

0.17

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.12

MutPred

0.19

Gain of relative solvent accessibility (P = 0.0522)

MVP

0.33

MPC

0.080

ClinPred

0.15

GERP RS

0.69

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.13

gMVP

0.24

Mutation Taster

=94/6

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over