Genetic Variant NOS3:c.2324+28C>T (chr7-151009295-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.2324+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,537,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000015 ( 0 hom., cov: 21)

Exomes 𝑓: 0.0000014 ( 0 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: 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 (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.2324+28C>T		intron_variant	Intron 19 of 26	ENST00000297494.8	NP_000594.2	P29474-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.2324+28C>T	intron_variant	Intron 19 of 26	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000461406.5 link	c.1706+28C>T	intron_variant	Intron 16 of 23	2		ENSP00000417143.1	E7ESA7
NOS3	ENST00000475017.1 link	c.203+28C>T	intron_variant	Intron 2 of 6	2		ENSP00000418245.1	H7C4V4
NOS3	ENST00000473057.1 link	n.268+28C>T	intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000149

AC:

AN:

134678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000534

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:

0.00

GnomAD2 exomes

AF:

0.00000440

AC:

AN:

227524

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000696

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

AF:

0.00000143

AC:

AN:

1402766

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698308

show subpopulations

African (AFR)

AF:

0.0000307

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:

9.38e-7

AC:

AN:

1066574

Other (OTH)

AF:

0.00

AC:

AN:

58080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000149

AC:

AN:

134678

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

65058

show subpopulations

African (AFR)

AF:

0.0000534

AC:

AN:

37420

American (AMR)

AF:

0.00

AC:

AN:

13302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3184

East Asian (EAS)

AF:

0.00

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: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

45793

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.1

(source)

DANN

Benign

0.76

PhyloP100

-2.9

PromoterAI

-0.024

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over