7-150996452-C-T

Variant summary

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

The NM_000603.5(NOS3):​c.319C>T​(p.Arg107Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,428,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.533
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=0.040333718).
BS2
High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOS3NM_000603.5 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 4/27 ENST00000297494.8 NP_000594.2 P29474-1
NOS3NM_001160111.1 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 3/14 NP_001153583.1 P29474-2
NOS3NM_001160110.1 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 3/14 NP_001153582.1 P29474-3
NOS3NM_001160109.2 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 3/14 NP_001153581.1 P29474A0S0A6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOS3ENST00000297494.8 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 4/271 NM_000603.5 ENSP00000297494.3 P29474-1
NOS3ENST00000484524.5 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 3/141 ENSP00000420215.1 P29474-2
NOS3ENST00000467517.1 linkuse as main transcriptc.319C>T p.Arg107Trp missense_variant 3/141 ENSP00000420551.1 P29474-3
NOS3ENST00000461406.5 linkuse as main transcriptc.-37+1138C>T intron_variant 2 ENSP00000417143.1 E7ESA7

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD3 exomes
AF:
0.0000879
AC:
17
AN:
193356
Hom.:
0
AF XY:
0.0000858
AC XY:
9
AN XY:
104882
show subpopulations
Gnomad AFR exome
AF:
0.0000902
Gnomad AMR exome
AF:
0.000450
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000769
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000217
AC:
31
AN:
1428016
Hom.:
0
Cov.:
34
AF XY:
0.0000226
AC XY:
16
AN XY:
707264
show subpopulations
Gnomad4 AFR exome
AF:
0.0000609
Gnomad4 AMR exome
AF:
0.000379
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000486
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000822
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
Cov.:
24
Alfa
AF:
0.0000277
Hom.:
0
ExAC
AF:
0.0000839
AC:
10

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 submitterclinical testingAmbry GeneticsApr 01, 2024The c.319C>T (p.R107W) alteration is located in exon 4 (coding exon 3) of the NOS3 gene. This alteration results from a C to T substitution at nucleotide position 319, causing the arginine (R) at amino acid position 107 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
0.17
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;.;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.11
N
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.040
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L;L;L
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.3
D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0080
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.55
MutPred
0.39
Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);
MVP
0.44
MPC
0.27
ClinPred
0.10
T
GERP RS
-2.5
Varity_R
0.26
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs767525655; hg19: chr7-150693540; API