7-150993921-C-G

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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 š‘“: 0.0000021 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.434
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06047198).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOS3NM_000603.5 linkc.118C>G p.Arg40Gly missense_variant Exon 2 of 27 ENST00000297494.8 NP_000594.2 P29474-1
NOS3NM_001160111.1 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 14 NP_001153583.1 P29474-2
NOS3NM_001160110.1 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 14 NP_001153582.1 P29474-3
NOS3NM_001160109.2 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 14 NP_001153581.1 P29474A0S0A6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOS3ENST00000297494.8 linkc.118C>G p.Arg40Gly missense_variant Exon 2 of 27 1 NM_000603.5 ENSP00000297494.3 P29474-1
NOS3ENST00000484524.5 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 14 1 ENSP00000420215.1 P29474-2
NOS3ENST00000467517.1 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 14 1 ENSP00000420551.1 P29474-3
NOS3ENST00000461406.5 linkc.-148-1282C>G intron_variant Intron 1 of 23 2 ENSP00000417143.1 E7ESA7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000210
AC:
3
AN:
1428664
Hom.:
0
Cov.:
31
AF XY:
0.00000282
AC XY:
2
AN XY:
708210
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:
0.00000273
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000865
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
6.9
DANN
Benign
0.92
DEOGEN2
Benign
0.12
T;.;.
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.060
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.11
N;N;N
REVEL
Benign
0.054
Sift
Benign
0.17
T;T;T
Sift4G
Benign
0.20
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.12
MutPred
0.19
Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);
MVP
0.33
MPC
0.080
ClinPred
0.15
T
GERP RS
0.69
Varity_R
0.13
gMVP
0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764652925; hg19: chr7-150691009; API