Genetic Variant NOS3:c.1821-62G>T (chr7-151006827-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000603.5(NOS3):c.1821-62G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,336,704 control chromosomes in the GnomAD database, including 197,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21116 hom., cov: 33)

Exomes 𝑓: 0.54 ( 176724 hom. )

Consequence

NOS3
NM_000603.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.50

Publications

24 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 7-151006827-G-T is Benign according to our data. Variant chr7-151006827-G-T is described in ClinVar as Benign. ClinVar VariationId is 1230779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.1821-62G>T		intron_variant	Intron 15 of 26	ENST00000297494.8	NP_000594.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8 link	c.1821-62G>T		intron_variant	Intron 15 of 26	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000461406.5 link	c.1203-62G>T		intron_variant	Intron 12 of 23	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79479

AN:

151988

Hom.:

21095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.615

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.608

Gnomad SAS

AF:

0.552

Gnomad FIN

AF:

0.516

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.523

GnomAD4 exome

AF:

0.544

AC:

645006

AN:

1184598

Hom.:

176724

AF XY:

0.544

AC XY:

327210

AN XY:

601612

show subpopulations

African (AFR)

AF:

0.463

AC:

13032

AN:

28124

American (AMR)

AF:

0.680

AC:

30016

AN:

44158

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

14283

AN:

24088

East Asian (EAS)

AF:

0.605

AC:

23237

AN:

38422

South Asian (SAS)

AF:

0.559

AC:

44371

AN:

79432

European-Finnish (FIN)

AF:

0.533

AC:

28061

AN:

52642

Middle Eastern (MID)

AF:

0.476

AC:

1880

AN:

3952

European-Non Finnish (NFE)

AF:

0.536

AC:

462579

AN:

862680

Other (OTH)

AF:

0.539

AC:

27547

AN:

51100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

15430

30860

46290

61720

77150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11872

23744

35616

47488

59360

<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:

0.523

AC:

79535

AN:

152106

Hom.:

21116

Cov.:

AF XY:

0.522

AC XY:

38804

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.468

AC:

19421

AN:

41516

American (AMR)

AF:

0.587

AC:

8985

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2068

AN:

3468

East Asian (EAS)

AF:

0.609

AC:

3143

AN:

5164

South Asian (SAS)

AF:

0.553

AC:

2669

AN:

4824

European-Finnish (FIN)

AF:

0.516

AC:

5445

AN:

10562

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.530

AC:

36005

AN:

67956

Other (OTH)

AF:

0.519

AC:

1096

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1972

3943

5915

7886

9858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.509

Hom.:

14666

Bravo

AF:

0.530

Asia WGS

AF:

0.538

AC:

1869

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.053

(source)

DANN

Benign

0.38

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over