dbSNP rs971095296: NOS3:p.Asp91Asn (chr7-150996404-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.271G>A(p.Asp91Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,378,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., cov: 14)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense, splice_region

Scores

Splicing: ADA: 0.7447

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

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:

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=0.18464082).

BS2

High AC in GnomAdExome4 at 42 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.271G>A	p.Asp91Asn	missense splice_region	Exon 4 of 27	NP_000594.2
NOS3	NM_001160111.1		c.271G>A	p.Asp91Asn	missense splice_region	Exon 3 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.271G>A	p.Asp91Asn	missense splice_region	Exon 3 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.271G>A	p.Asp91Asn	missense splice_region	Exon 4 of 27	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.271G>A	p.Asp91Asn	missense splice_region	Exon 3 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.271G>A	p.Asp91Asn	missense splice_region	Exon 3 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.00000906

AC:

AN:

110418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000726

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

155154

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:

0.0000341

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000331

AC:

AN:

1268234

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

624354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28202

American (AMR)

AF:

0.00

AC:

AN:

31670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20052

East Asian (EAS)

AF:

0.00

AC:

AN:

24656

South Asian (SAS)

AF:

0.00

AC:

AN:

78256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4976

European-Non Finnish (NFE)

AF:

0.0000372

AC:

AN:

995684

Other (OTH)

AF:

0.000102

AC:

AN:

49182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00000906

AC:

AN:

110418

Hom.:

Cov.:

AF XY:

0.0000191

AC XY:

AN XY:

52360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27744

American (AMR)

AF:

0.00

AC:

AN:

10292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2854

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.00

AC:

AN:

2570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54544

Other (OTH)

AF:

0.000726

AC:

AN:

1378

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

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:

0.0000579

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions as Germline

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

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.68

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Benign

-0.17

Eigen_PC

Benign

0.017

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0097

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

2.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

REVEL

Benign

0.069

Sift

Benign

0.62

Sift4G

Benign

0.49

Polyphen

0.0

Vest4

0.32

MVP

0.62

MPC

0.080

ClinPred

0.11

GERP RS

4.9

Varity_R

0.27

gMVP

0.21

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.74

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.11

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