Genetic Variant NOS3:c.1752+142_1752+149delACACACAC (chr7-151002383-AACACACAC-A) – 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+142_1752+149delACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 270,812 control chromosomes in the GnomAD database, including 123 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.045 ( 119 hom., cov: 0)

Exomes 𝑓: 0.0052 ( 4 hom. )

Consequence

NOS3
NM_000603.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.908

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 (NFE) allele frequency at 95% confidence interval = 0.0502 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+142_1752+149delACACACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+142_1752+149delACACACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+142_1752+149delACACACAC	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+80_1752+87delACACACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+87delACACACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+87delACACACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0449

AC:

2923

AN:

65102

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0334

Gnomad AMI

AF:

0.0438

Gnomad AMR

AF:

0.0499

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.0406

Gnomad SAS

AF:

0.0495

Gnomad FIN

AF:

0.0403

Gnomad MID

AF:

0.0929

Gnomad NFE

AF:

0.0523

Gnomad OTH

AF:

0.0398

GnomAD4 exome

AF:

0.00524

AC:

1078

AN:

205650

Hom.:

AF XY:

0.00548

AC XY:

624

AN XY:

113846

show subpopulations

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

African (AFR)

AF:

0.00278

AC:

AN:

6832

American (AMR)

AF:

0.00189

AC:

AN:

19012

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

6864

East Asian (EAS)

AF:

0.00454

AC:

AN:

7488

South Asian (SAS)

AF:

0.00508

AC:

196

AN:

38560

European-Finnish (FIN)

AF:

0.00601

AC:

AN:

9814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

840

European-Non Finnish (NFE)

AF:

0.00613

AC:

650

AN:

106110

Other (OTH)

AF:

0.00632

AC:

AN:

10130

⚠️ 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: 0.383

Heterozygous variant carriers

116

174

232

290

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:

0.0449

AC:

2925

AN:

65162

Hom.:

119

Cov.:

AF XY:

0.0443

AC XY:

1329

AN XY:

30020

show subpopulations

African (AFR)

AF:

0.0335

AC:

592

AN:

17656

American (AMR)

AF:

0.0504

AC:

281

AN:

5578

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

2004

East Asian (EAS)

AF:

0.0403

AC:

AN:

2310

South Asian (SAS)

AF:

0.0486

AC:

AN:

1564

European-Finnish (FIN)

AF:

0.0403

AC:

112

AN:

2776

Middle Eastern (MID)

AF:

0.0833

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0523

AC:

1664

AN:

31844

Other (OTH)

AF:

0.0405

AC:

AN:

864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

101

203

304

406

507

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

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