Genetic Variant NM_000603.5:c.1752+120_1752+149delACACACACACACACACACACACACACACAC (chr7-151002383-AACACACACACACACACACACACACACACAC-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000603.5(NOS3):c.1752+120_1752+149delACACACACACACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 271,058 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 0)

Exomes 𝑓: 0.00087 ( 0 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 219 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
NOS3	NM_000603.5	MANE Select	c.1752+120_1752+149delACACACACACACACACACACACACACACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+120_1752+149delACACACACACACACACACACACACACACAC	intron	N/A	NP_001153583.1
NOS3	NM_001160110.1		c.1752+120_1752+149delACACACACACACACACACACACACACACAC	intron	N/A	NP_001153582.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1752+80_1752+109delACACACACACACACACACACACACACACAC	intron	N/A	ENSP00000297494.3
NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+109delACACACACACACACACACACACACACACAC	intron	N/A	ENSP00000420215.1
NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+109delACACACACACACACACACACACACACACAC	intron	N/A	ENSP00000420551.1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

220

AN:

65214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00377

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000432

Gnomad SAS

AF:

0.000633

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000407

Gnomad OTH

AF:

0.00583

GnomAD4 exome

AF:

0.000875

AC:

180

AN:

205786

Hom.:

AF XY:

0.000869

AC XY:

AN XY:

113932

show subpopulations

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

African (AFR)

AF:

0.00293

AC:

AN:

6828

American (AMR)

AF:

0.000526

AC:

AN:

19012

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

6860

East Asian (EAS)

AF:

0.00200

AC:

AN:

7490

South Asian (SAS)

AF:

0.00101

AC:

AN:

38612

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

9822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

106176

Other (OTH)

AF:

0.000690

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: 0.396

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:

0.00336

AC:

219

AN:

65272

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

AN XY:

30076

show subpopulations

African (AFR)

AF:

0.0101

AC:

179

AN:

17690

American (AMR)

AF:

0.00376

AC:

AN:

5584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2006

East Asian (EAS)

AF:

0.000433

AC:

AN:

2310

South Asian (SAS)

AF:

0.00

AC:

AN:

1566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.000407

AC:

AN:

31904

Other (OTH)

AF:

0.00576

AC:

AN:

868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.582

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

Mutation Taster

=92/8

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