Genetic Variant NOS3:c.2324+28C>G (chr7-151009295-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000603.5(NOS3):c.2324+28C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,537,444 control chromosomes in the GnomAD database, including 1 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 0.00014 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000011 ( 1 hom. )

Consequence

NOS3
NM_000603.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.89

Publications

25 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BS2

High AC in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.2324+28C>G		intron	N/A	NP_000594.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.2324+28C>G	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000943234.1		c.2324+28C>G	intron	N/A	ENSP00000613293.1
NOS3	ENST00000908206.1		c.2324+28C>G	intron	N/A	ENSP00000578265.1

Frequencies

GnomAD3 genomes

AF:

0.000141

AC:

AN:

134678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000231

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000308

AC:

AN:

227524

AF XY:

0.0000163

show subpopulations

Gnomad AFR exome

AF:

0.000348

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:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1402766

Hom.:

Cov.:

AF XY:

0.00000859

AC XY:

AN XY:

698308

show subpopulations

African (AFR)

AF:

0.000399

AC:

AN:

32542

American (AMR)

AF:

0.00

AC:

AN:

42286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

38170

South Asian (SAS)

AF:

0.00

AC:

AN:

83504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1066574

Other (OTH)

AF:

0.00

AC:

AN:

58080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000141

AC:

AN:

134678

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

65058

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

37420

American (AMR)

AF:

0.00

AC:

AN:

13302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3184

East Asian (EAS)

AF:

0.000231

AC:

AN:

4334

South Asian (SAS)

AF:

0.00

AC:

AN:

4040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61254

Other (OTH)

AF:

0.00

AC:

AN:

1846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

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.:

45793

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.91

(source)

DANN

Benign

0.27

PhyloP100

-2.9

PromoterAI

-0.057

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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