Genetic Variant NM_000603.5:c.1752+146_1752+149delACAC (chr7-151002383-AACAC-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+146_1752+149delACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 270,660 control chromosomes in the GnomAD database, including 149 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.055 ( 148 hom., cov: 0)

Exomes 𝑓: 0.0030 ( 1 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 = 0.0734 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+146_1752+149delACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+146_1752+149delACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+146_1752+149delACAC	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+83delACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+83delACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+83delACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0551

AC:

3583

AN:

64980

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0354

Gnomad AMI

AF:

0.0276

Gnomad AMR

AF:

0.0795

Gnomad ASJ

AF:

0.0531

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.0460

Gnomad FIN

AF:

0.0630

Gnomad MID

AF:

0.0857

Gnomad NFE

AF:

0.0626

Gnomad OTH

AF:

0.0526

GnomAD4 exome

AF:

0.00300

AC:

617

AN:

205620

Hom.:

AF XY:

0.00312

AC XY:

355

AN XY:

113848

show subpopulations

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

African (AFR)

AF:

0.00103

AC:

AN:

6824

American (AMR)

AF:

0.000789

AC:

AN:

19014

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

6860

East Asian (EAS)

AF:

0.00334

AC:

AN:

7490

South Asian (SAS)

AF:

0.00283

AC:

109

AN:

38580

European-Finnish (FIN)

AF:

0.00408

AC:

AN:

9810

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.00358

AC:

380

AN:

106074

Other (OTH)

AF:

0.00227

AC:

AN:

10126

⚠️ 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: 0.354

Heterozygous variant carriers

118

157

196

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:

0.0551

AC:

3582

AN:

65040

Hom.:

148

Cov.:

AF XY:

0.0562

AC XY:

1683

AN XY:

29962

show subpopulations

African (AFR)

AF:

0.0353

AC:

623

AN:

17626

American (AMR)

AF:

0.0796

AC:

443

AN:

5568

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

106

AN:

1996

East Asian (EAS)

AF:

0.0460

AC:

106

AN:

2304

South Asian (SAS)

AF:

0.0457

AC:

AN:

1554

European-Finnish (FIN)

AF:

0.0630

AC:

174

AN:

2760

Middle Eastern (MID)

AF:

0.0833

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0626

AC:

1991

AN:

31800

Other (OTH)

AF:

0.0520

AC:

AN:

866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

117

235

352

470

587

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