Genetic Variant NM_000603.5:c.1752+148_1752+149delAC (chr7-151002383-AAC-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+148_1752+149delAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 270,808 control chromosomes in the GnomAD database, including 95 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.045 ( 95 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 0 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 = 0.0634 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+149delAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+148_1752+149delAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+148_1752+149delAC	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+81delAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+81delAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+81delAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

2940

AN:

65038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.0161

Gnomad AMR

AF:

0.0692

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.0330

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.0357

Gnomad NFE

AF:

0.0544

Gnomad OTH

AF:

0.0505

GnomAD4 exome

AF:

0.00153

AC:

314

AN:

205714

Hom.:

AF XY:

0.00160

AC XY:

182

AN XY:

113892

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:

6830

American (AMR)

AF:

0.000578

AC:

AN:

19016

Ashkenazi Jewish (ASJ)

AF:

0.000437

AC:

AN:

6862

East Asian (EAS)

AF:

0.00200

AC:

AN:

7484

South Asian (SAS)

AF:

0.000699

AC:

AN:

38600

European-Finnish (FIN)

AF:

0.00285

AC:

AN:

9808

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.00198

AC:

210

AN:

106134

Other (OTH)

AF:

0.00118

AC:

AN:

10138

⚠️ 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: 0.358

Heterozygous variant carriers

108

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:

0.0452

AC:

2941

AN:

65094

Hom.:

Cov.:

AF XY:

0.0447

AC XY:

1341

AN XY:

30006

show subpopulations

African (AFR)

AF:

0.0263

AC:

463

AN:

17636

American (AMR)

AF:

0.0691

AC:

385

AN:

5572

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

AN:

2002

East Asian (EAS)

AF:

0.0403

AC:

AN:

2306

South Asian (SAS)

AF:

0.0321

AC:

AN:

1560

European-Finnish (FIN)

AF:

0.0361

AC:

100

AN:

2772

Middle Eastern (MID)

AF:

0.0379

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0544

AC:

1730

AN:

31818

Other (OTH)

AF:

0.0499

AC:

AN:

862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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