Genetic Variant NOS3:p.Pro58Ala (chr7-150995216-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_000603.5(NOS3):c.172C>G(p.Pro58Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,246 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. P58S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.20

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150995216-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 929757.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.09314731).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	NM_000603.5	MANE Select	c.172C>G	p.Pro58Ala	missense	Exon 3 of 27	NP_000594.2
NOS3	NM_001160111.1		c.172C>G	p.Pro58Ala	missense	Exon 2 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.172C>G	p.Pro58Ala	missense	Exon 2 of 14	NP_001153582.1	P29474-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.172C>G	p.Pro58Ala	missense	Exon 3 of 27	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.172C>G	p.Pro58Ala	missense	Exon 2 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.172C>G	p.Pro58Ala	missense	Exon 2 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456246

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108552

Other (OTH)

AF:

0.00

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.099

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.62

M_CAP

Benign

0.0071

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

PhyloP100

1.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.25

REVEL

Benign

0.038

Sift

Benign

0.48

Sift4G

Benign

0.45

Polyphen

0.0040

Vest4

0.16

MutPred

0.17

Loss of glycosylation at P58 (P = 0.0102)

MVP

0.53

MPC

0.28

ClinPred

0.28

GERP RS

3.3

Varity_R

0.044

gMVP

0.15

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over