Genetic Variant NOS3:p.Pro1003Ser (chr7-151012373-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000603.5(NOS3):c.3007C>T(p.Pro1003Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1003P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Publications

1 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:

ATG9B (HGNC:21899): (autophagy related 9B) This gene functions in the regulation of autophagy, a lysosomal degradation pathway. This gene also functions as an antisense transcript in the posttranscriptional regulation of the endothelial nitric oxide synthase 3 gene, which has 3' overlap with this gene on the opposite strand. Mutations in this gene and disruption of the autophagy process have been associated with multiple cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

ATG9B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045708716).

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
NOS3	NM_000603.5	MANE Select	c.3007C>T	p.Pro1003Ser	missense	Exon 24 of 27	NP_000594.2
ATG9B	NR_073169.1		n.3676G>A		non_coding_transcript_exon	Exon 18 of 18
ATG9B	NR_133652.1		n.4413G>A		non_coding_transcript_exon	Exon 17 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.3007C>T	p.Pro1003Ser	missense	Exon 24 of 27	ENSP00000297494.3	P29474-1
ATG9B	ENST00000605952.5	TSL:1	n.*1562G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000475737.2	Q674R7-1
ATG9B	ENST00000605952.5	TSL:1	n.*1562G>A		3_prime_UTR	Exon 17 of 17	ENSP00000475737.2	Q674R7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

196188

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1427054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705984

African (AFR)

AF:

0.00

AC:

AN:

33190

American (AMR)

AF:

0.00

AC:

AN:

37760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25400

East Asian (EAS)

AF:

0.00

AC:

AN:

38706

South Asian (SAS)

AF:

0.00

AC:

AN:

81356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094614

Other (OTH)

AF:

0.00

AC:

AN:

59224

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.11

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.81

M_CAP

Benign

0.0067

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.93

PhyloP100

1.8

PrimateAI

Benign

0.33

PROVEAN

Benign

0.64

REVEL

Benign

0.081

Sift

Benign

0.54

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.19

MutPred

0.25

Loss of catalytic residue at P1002 (P = 0.0108)

MVP

0.63

MPC

0.50

ClinPred

0.17

GERP RS

3.9

Varity_R

0.077

gMVP

0.47

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over