Genetic Variant NOS3:p.Arg112Pro (chr7-150996468-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000603.5(NOS3):c.335G>C(p.Arg112Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,590,188 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. R112Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015100747).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.335G>C	p.Arg112Pro	missense_variant	Exon 4 of 27	ENST00000297494.8	NP_000594.2	P29474-1
NOS3	NM_001160111.1 link	c.335G>C	p.Arg112Pro	missense_variant	Exon 3 of 14		NP_001153583.1	P29474-2
NOS3	NM_001160110.1 link	c.335G>C	p.Arg112Pro	missense_variant	Exon 3 of 14		NP_001153582.1	P29474-3
NOS3	NM_001160109.2 link	c.335G>C	p.Arg112Pro	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>C	p.Arg112Pro	missense_variant	Exon 4 of 27	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5 link	c.335G>C	p.Arg112Pro	missense_variant	Exon 3 of 14	1		ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1 link	c.335G>C	p.Arg112Pro	missense_variant	Exon 3 of 14	1		ENSP00000420551.1	P29474-3
NOS3	ENST00000461406.5 link	c.-37+1154G>C		intron_variant	Intron 2 of 23	2		ENSP00000417143.1	E7ESA7

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000205

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000877

AC:

AN:

216676

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000597

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:

0.0000111

AC:

AN:

1444138

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

716682

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33174

American (AMR)

AF:

0.000377

AC:

AN:

42408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25726

East Asian (EAS)

AF:

0.00

AC:

AN:

39120

South Asian (SAS)

AF:

0.00

AC:

AN:

83960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103632

Other (OTH)

AF:

0.00

AC:

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.0000205

AC:

AN:

146050

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38996

American (AMR)

AF:

0.000205

AC:

AN:

14630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

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:

0.00

AC:

AN:

66566

Other (OTH)

AF:

0.00

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000919

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.0044

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L

PhyloP100

0.28

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0070

B;.;.

Vest4

0.19

MutPred

0.32

Gain of glycosylation at R112 (P = 0.0038);Gain of glycosylation at R112 (P = 0.0038);Gain of glycosylation at R112 (P = 0.0038);

MVP

0.53

MPC

0.091

ClinPred

0.047

GERP RS

3.9

Varity_R

0.32

gMVP

0.67

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over