Genetic Variant NOS3:c.1752+148_1752+149dupAC (chr7-151002383-A-AAC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000603.5(NOS3):c.1752+148_1752+149dupAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 270,932 control chromosomes in the GnomAD database, including 301 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 273 hom., cov: 0)

Exomes 𝑓: 0.0013 ( 28 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.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

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+148_1752+149dupAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+148_1752+149dupAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+148_1752+149dupAC	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+80insAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+79_1752+80insAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+79_1752+80insAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

3326

AN:

65098

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0611

Gnomad ASJ

AF:

0.0459

Gnomad EAS

AF:

0.0537

Gnomad SAS

AF:

0.0305

Gnomad FIN

AF:

0.0466

Gnomad MID

AF:

0.0357

Gnomad NFE

AF:

0.0590

Gnomad OTH

AF:

0.0434

GnomAD4 exome

AF:

0.00128

AC:

264

AN:

205774

Hom.:

AF XY:

0.00129

AC XY:

147

AN XY:

113920

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000878

AC:

AN:

6832

American (AMR)

AF:

0.000263

AC:

AN:

19014

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

6864

East Asian (EAS)

AF:

0.00200

AC:

AN:

7486

South Asian (SAS)

AF:

0.000855

AC:

AN:

38604

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

9818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.00161

AC:

171

AN:

106170

Other (OTH)

AF:

0.00118

AC:

AN:

10144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

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:

0.0511

AC:

3327

AN:

65158

Hom.:

273

Cov.:

AF XY:

0.0514

AC XY:

1542

AN XY:

30020

show subpopulations

African (AFR)

AF:

0.0371

AC:

656

AN:

17668

American (AMR)

AF:

0.0610

AC:

339

AN:

5558

Ashkenazi Jewish (ASJ)

AF:

0.0459

AC:

AN:

2004

East Asian (EAS)

AF:

0.0539

AC:

124

AN:

2302

South Asian (SAS)

AF:

0.0307

AC:

AN:

1562

European-Finnish (FIN)

AF:

0.0466

AC:

129

AN:

2766

Middle Eastern (MID)

AF:

0.0379

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0590

AC:

1879

AN:

31872

Other (OTH)

AF:

0.0429

AC:

AN:

862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

133

265

398

530

663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0372

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 (auto)

(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