dbSNP rs3730006: NOS3:c.2245+27G>A (chr7-151009089-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000603.5(NOS3):c.2245+27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,612,764 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.021 ( 33 hom., cov: 33)

Exomes 𝑓: 0.022 ( 428 hom. )

Consequence

NOS3
NM_000603.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.708

Publications

6 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.2245+27G>A		intron_variant	Intron 18 of 26	ENST00000297494.8	NP_000594.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
NOS3	ENST00000297494.8 link	c.2245+27G>A	intron_variant	Intron 18 of 26	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000461406.5 link	c.1627+27G>A	intron_variant	Intron 15 of 23	2		ENSP00000417143.1
NOS3	ENST00000475017.1 link	c.124+27G>A	intron_variant	Intron 1 of 6	2		ENSP00000418245.1
NOS3	ENST00000473057.1 link	n.189+27G>A	intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0207

AC:

3148

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00696

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0242

Gnomad OTH

AF:

0.0460

GnomAD2 exomes

AF:

0.0187

AC:

4623

AN:

246770

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0314

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.00985

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0216

AC:

31617

AN:

1460530

Hom.:

428

Cov.:

AF XY:

0.0215

AC XY:

15633

AN XY:

726538

show subpopulations

African (AFR)

AF:

0.0196

AC:

654

AN:

33436

American (AMR)

AF:

0.0204

AC:

909

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.0319

AC:

830

AN:

26034

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.00724

AC:

624

AN:

86144

European-Finnish (FIN)

AF:

0.00970

AC:

515

AN:

53100

Middle Eastern (MID)

AF:

0.0602

AC:

347

AN:

5762

European-Non Finnish (NFE)

AF:

0.0235

AC:

26119

AN:

1111514

Other (OTH)

AF:

0.0268

AC:

1617

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1659

3319

4978

6638

8297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

974

1948

2922

3896

4870

<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:

0.0207

AC:

3152

AN:

152234

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1470

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0178

AC:

739

AN:

41534

American (AMR)

AF:

0.0275

AC:

421

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00696

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0242

AC:

1646

AN:

67992

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

157

314

471

628

785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0238

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.7

(source)

DANN

Benign

0.48

PhyloP100

0.71

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over