Genetic Variant NM_000603.5:c.2479G>C (chr7-151009552-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000603.5(NOS3):c.2479G>C(p.Val827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,310 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. V827M) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.51

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16410542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.2479G>C	p.Val827Leu	missense_variant	Exon 20 of 27	ENST00000297494.8	NP_000594.2	P29474-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.2479G>C	p.Val827Leu	missense_variant	Exon 20 of 27	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000461406.5 link	c.1861G>C	p.Val621Leu	missense_variant	Exon 17 of 24	2		ENSP00000417143.1	E7ESA7
NOS3	ENST00000475017.1 link	c.358G>C	p.Val120Leu	missense_variant	Exon 3 of 7	2		ENSP00000418245.1	H7C4V4
NOS3	ENST00000473057.1 link	n.423G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1391310

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685926

show subpopulations

African (AFR)

AF:

0.0000318

AC:

AN:

31468

American (AMR)

AF:

0.00

AC:

AN:

35450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25020

East Asian (EAS)

AF:

0.00

AC:

AN:

35676

South Asian (SAS)

AF:

0.00

AC:

AN:

78882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4786

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077086

Other (OTH)

AF:

0.00

AC:

AN:

57694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

L;.

PhyloP100

2.5

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.12

Sift

Benign

0.27

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.058

B;B

Vest4

0.19

MutPred

0.55

Gain of glycosylation at P826 (P = 0.1266);.;

MVP

0.66

MPC

0.58

ClinPred

0.45

GERP RS

-0.10

Varity_R

0.072

gMVP

0.35

Mutation Taster

=92/8

polymorphism

(source)

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

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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