Genetic Variant NM_000603.5:c.1752+138_1752+149dupACACACACACAC (chr7-151002383-A-AACACACACACAC) – 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+138_1752+149dupACACACACACAC 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 0.0029 ( 15 hom., cov: 0)

Exomes 𝑓: 0.00012 ( 0 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 190 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+138_1752+149dupACACACACACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+138_1752+149dupACACACACACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+138_1752+149dupACACACACACAC	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+80insACACACACACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+79_1752+80insACACACACACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+79_1752+80insACACACACACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

190

AN:

65210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00485

Gnomad ASJ

AF:

0.00499

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00190

Gnomad FIN

AF:

0.000720

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00320

Gnomad OTH

AF:

0.00583

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000117

AC:

AN:

205824

Hom.:

AF XY:

0.000114

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:

0.000146

AC:

AN:

6864

East Asian (EAS)

AF:

0.00

AC:

AN:

7492

South Asian (SAS)

AF:

0.000207

AC:

AN:

38614

European-Finnish (FIN)

AF:

0.000305

AC:

AN:

9822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

106196

Other (OTH)

AF:

0.0000986

AC:

AN:

10144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.652

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:

0.00291

AC:

190

AN:

65268

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

AN XY:

30072

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

17688

American (AMR)

AF:

0.00484

AC:

AN:

5582

Ashkenazi Jewish (ASJ)

AF:

0.00499

AC:

AN:

2006

East Asian (EAS)

AF:

0.00173

AC:

AN:

2310

South Asian (SAS)

AF:

0.00192

AC:

AN:

1566

European-Finnish (FIN)

AF:

0.000720

AC:

AN:

2778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.00320

AC:

102

AN:

31904

Other (OTH)

AF:

0.00576

AC:

AN:

868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.560

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

Alfa

AF:

0.00

Hom.:

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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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