7-150993921-C-T

Variant summary

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

The NM_000603.5(NOS3):​c.118C>T​(p.Arg40Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,580,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

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=0.05912873).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOS3NM_000603.5 linkc.118C>T p.Arg40Trp missense_variant Exon 2 of 27 ENST00000297494.8 NP_000594.2 P29474-1
NOS3NM_001160111.1 linkc.118C>T p.Arg40Trp missense_variant Exon 1 of 14 NP_001153583.1 P29474-2
NOS3NM_001160110.1 linkc.118C>T p.Arg40Trp missense_variant Exon 1 of 14 NP_001153582.1 P29474-3
NOS3NM_001160109.2 linkc.118C>T p.Arg40Trp 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>T p.Arg40Trp missense_variant Exon 2 of 27 1 NM_000603.5 ENSP00000297494.3 P29474-1
NOS3ENST00000484524.5 linkc.118C>T p.Arg40Trp missense_variant Exon 1 of 14 1 ENSP00000420215.1 P29474-2
NOS3ENST00000467517.1 linkc.118C>T p.Arg40Trp missense_variant Exon 1 of 14 1 ENSP00000420551.1 P29474-3
NOS3ENST00000461406.5 linkc.-148-1282C>T intron_variant Intron 1 of 23 2 ENSP00000417143.1 E7ESA7

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152042
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000323
AC:
6
AN:
185948
Hom.:
0
AF XY:
0.00000983
AC XY:
1
AN XY:
101718
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000704
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000511
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000903
AC:
129
AN:
1428664
Hom.:
0
Cov.:
31
AF XY:
0.0000988
AC XY:
70
AN XY:
708210
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
Gnomad4 AMR exome
AF:
0.0000499
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000242
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000108
Gnomad4 OTH exome
AF:
0.0000678
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152042
Hom.:
0
Cov.:
33
AF XY:
0.0000539
AC XY:
4
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000308
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000433
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.118C>T (p.R40W) alteration is located in exon 2 (coding exon 1) of the NOS3 gene. This alteration results from a C to T substitution at nucleotide position 118, causing the arginine (R) at amino acid position 40 to be replaced by a tryptophan (W). 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
0.090
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;.;.
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.0097
T
MetaRNN
Benign
0.059
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.081
Sift
Benign
0.064
T;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
0.0
B;.;.
Vest4
0.086
MutPred
0.17
Gain of glycosylation at P36 (P = 0.0924);Gain of glycosylation at P36 (P = 0.0924);Gain of glycosylation at P36 (P = 0.0924);
MVP
0.33
MPC
0.066
ClinPred
0.11
T
GERP RS
0.69
Varity_R
0.044
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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; COSMIC: COSV104626372; API