Genetic Variant NOS3:c.1752+144_1752+149dupACACAC (chr7-151002383-A-AACACAC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000603.5(NOS3):c.1752+144_1752+149dupACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 271,030 control chromosomes in the GnomAD database, including 164 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 129 hom., cov: 0)

Exomes 𝑓: 0.0011 ( 35 hom. )

Consequence

NOS3
NM_000603.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.222

Publications

9 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.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0222 (1445/65214) while in subpopulation NFE AF = 0.0277 (884/31886). AF 95% confidence interval is 0.0262. There are 129 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 1445 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	Effect	Exon Rank	Protein	UniProt
NOS3	NM_000603.5	MANE Select	c.1752+144_1752+149dupACACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+144_1752+149dupACACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+144_1752+149dupACACAC	intron	N/A	NP_001153582.1	P29474-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1752+79_1752+80insACACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+79_1752+80insACACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+79_1752+80insACACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

1445

AN:

65152

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.00691

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.0152

Gnomad SAS

AF:

0.00888

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.0143

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0292

GnomAD4 exome

AF:

0.00111

AC:

229

AN:

205816

Hom.:

AF XY:

0.00112

AC XY:

128

AN XY:

113946

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

6830

American (AMR)

AF:

0.000210

AC:

AN:

19016

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

6864

East Asian (EAS)

AF:

0.00160

AC:

AN:

7492

South Asian (SAS)

AF:

0.00114

AC:

AN:

38610

European-Finnish (FIN)

AF:

0.000713

AC:

AN:

9822

Middle Eastern (MID)

AF:

0.00475

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.00130

AC:

138

AN:

106196

Other (OTH)

AF:

0.000887

AC:

AN:

10144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

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:

0.0222

AC:

1445

AN:

65214

Hom.:

129

Cov.:

AF XY:

0.0225

AC XY:

675

AN XY:

30048

show subpopulations

African (AFR)

AF:

0.0152

AC:

269

AN:

17670

American (AMR)

AF:

0.0231

AC:

129

AN:

5584

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

2006

East Asian (EAS)

AF:

0.0156

AC:

AN:

2302

South Asian (SAS)

AF:

0.00896

AC:

AN:

1562

European-Finnish (FIN)

AF:

0.0166

AC:

AN:

2772

Middle Eastern (MID)

AF:

0.0152

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0277

AC:

884

AN:

31886

Other (OTH)

AF:

0.0289

AC:

AN:

866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.556

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0227

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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