Genetic Variant NOS3:c.1752+136_1752+149dupACACACACACACAC (chr7-151002383-A-AACACACACACACAC) – 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+136_1752+149dupACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.00090 ( 6 hom., cov: 0)

Exomes 𝑓: 0.000049 ( 1 hom. )

Failed GnomAD Quality Control

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 59 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+136_1752+149dupACACACACACACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+136_1752+149dupACACACACACACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+136_1752+149dupACACACACACACAC	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+80insACACACACACACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+79_1752+80insACACACACACACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+79_1752+80insACACACACACACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

AN:

65212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00150

Gnomad EAS

AF:

0.00130

Gnomad SAS

AF:

0.00253

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000940

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000486

AC:

AN:

205824

Hom.:

AF XY:

0.0000527

AC XY:

AN XY:

113952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6834

American (AMR)

AF:

0.00

AC:

AN:

19016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6864

East Asian (EAS)

AF:

0.00

AC:

AN:

7492

South Asian (SAS)

AF:

0.000129

AC:

AN:

38614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

106196

Other (OTH)

AF:

0.0000986

AC:

AN:

10144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.594

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:

0.000904

AC:

AN:

65270

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

30074

show subpopulations

African (AFR)

AF:

0.000678

AC:

AN:

17688

American (AMR)

AF:

0.00143

AC:

AN:

5584

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

2006

East Asian (EAS)

AF:

0.00130

AC:

AN:

2310

South Asian (SAS)

AF:

0.00192

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:

0.000940

AC:

AN:

31904

Other (OTH)

AF:

0.00

AC:

AN:

868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.22

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACACACACACACACACACACACACACACACACACACACACAC

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