Genetic Variant NM_000603.5:c.1752+146_1752+149dupACAC (chr7-151002383-A-AACAC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000603.5(NOS3):c.1752+146_1752+149dupACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00977 in 270,980 control chromosomes in the GnomAD database, including 235 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 197 hom., cov: 0)

Exomes 𝑓: 0.0011 ( 38 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.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.037 (2412/65198) while in subpopulation NFE AF = 0.0447 (1424/31892). AF 95% confidence interval is 0.0427. There are 197 homozygotes in GnomAd4. There are 1082 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 2412 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+146_1752+149dupACAC	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.1752+146_1752+149dupACAC	intron	N/A	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.1752+146_1752+149dupACAC	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+80insACAC	intron	N/A	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.1752+79_1752+80insACAC	intron	N/A	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.1752+79_1752+80insACAC	intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

2414

AN:

65140

Hom.:

197

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0243

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0446

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.0372

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.0400

Gnomad MID

AF:

0.0429

Gnomad NFE

AF:

0.0446

Gnomad OTH

AF:

0.0386

GnomAD4 exome

AF:

0.00115

AC:

236

AN:

205782

Hom.:

AF XY:

0.00114

AC XY:

130

AN XY:

113928

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

6832

American (AMR)

AF:

0.000210

AC:

AN:

19016

Ashkenazi Jewish (ASJ)

AF:

0.000874

AC:

AN:

6862

East Asian (EAS)

AF:

0.000668

AC:

AN:

7490

South Asian (SAS)

AF:

0.00122

AC:

AN:

38610

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

9818

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

842

European-Non Finnish (NFE)

AF:

0.00127

AC:

135

AN:

106176

Other (OTH)

AF:

0.00109

AC:

AN:

10136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0370

AC:

2412

AN:

65198

Hom.:

197

Cov.:

AF XY:

0.0360

AC XY:

1082

AN XY:

30028

show subpopulations

African (AFR)

AF:

0.0241

AC:

426

AN:

17654

American (AMR)

AF:

0.0445

AC:

248

AN:

5570

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

2006

East Asian (EAS)

AF:

0.0369

AC:

AN:

2306

South Asian (SAS)

AF:

0.0160

AC:

AN:

1566

European-Finnish (FIN)

AF:

0.0400

AC:

111

AN:

2772

Middle Eastern (MID)

AF:

0.0455

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0447

AC:

1424

AN:

31892

Other (OTH)

AF:

0.0381

AC:

AN:

866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0187

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 (auto)

(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