dbSNP rs1417289111: NOS3:p.Ala86Thr (chr7-150995300-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000603.5(NOS3):c.256G>A(p.Ala86Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,610,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0905506).

BS2

High AC in GnomAdExome4 at 70 AD gene.

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.256G>A	p.Ala86Thr	missense	Exon 3 of 27	NP_000594.2
NOS3	NM_001160111.1		c.256G>A	p.Ala86Thr	missense	Exon 2 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.256G>A	p.Ala86Thr	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.256G>A	p.Ala86Thr	missense	Exon 3 of 27	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.256G>A	p.Ala86Thr	missense	Exon 2 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.256G>A	p.Ala86Thr	missense	Exon 2 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

247966

AF XY:

0.00

show subpopulations

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:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000480

AC:

AN:

1458074

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

725378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000604

AC:

AN:

1110140

Other (OTH)

AF:

0.0000166

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

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

0.083

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.79

M_CAP

Benign

0.0076

MetaRNN

Benign

0.091

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.30

REVEL

Benign

0.029

Sift

Benign

0.41

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.33

MutPred

0.21

Loss of sheet (P = 0.0457)

MVP

0.28

MPC

0.063

ClinPred

0.23

GERP RS

3.3

Varity_R

0.12

gMVP

0.18

Mutation Taster

=71/29

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over