Variant chr7-150996497-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000603.5(NOS3):c.364C>G(p.Gln122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,605,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.398

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027166873).

BS2

High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NOS3	NM_000603.5 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	4/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	3/14		NP_001153583.1
NOS3	NM_001160110.1 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	3/14		NP_001153582.1
NOS3	NM_001160109.2 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	3/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	4/27	1	NM_000603.5	ENSP00000297494	P1	P29474-1
NOS3	ENST00000484524.5 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	3/14	1		ENSP00000420215		P29474-2
NOS3	ENST00000467517.1 linkuse as main transcript	c.364C>G	p.Gln122Glu	missense_variant	3/14	1		ENSP00000420551		P29474-3
NOS3	ENST00000461406.5 linkuse as main transcript	c.-37+1183C>G		intron_variant		2		ENSP00000417143

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000495

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1457678

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

724878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71956

show subpopulations

Gnomad4 AFR

AF:

0.0000251

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000490

Bravo

AF:

0.00000378

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.364C>G (p.Q122E) alteration is located in exon 4 (coding exon 3) of the NOS3 gene. This alteration results from a C to G substitution at nucleotide position 364, causing the glutamine (Q) at amino acid position 122 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.065

T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0017

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;N;N

MutationTaster

Benign

0.82

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

1.3

N;N;N

REVEL

Benign

0.071

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.074

MVP

0.36

MPC

0.068

ClinPred

0.064

GERP RS

4.1

Varity_R

0.24

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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