Genetic Variant ENST00000484524.5:c.*570C>A (chr7-151003858-C-A) – 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 ENST00000484524.5(NOS3):c.*570C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 396,480 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 491 hom., cov: 32)

Exomes 𝑓: 0.083 ( 946 hom. )

Consequence

NOS3
ENST00000484524.5 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.968

Publications

47 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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new If you want to explore the variant's impact on the transcript ENST00000484524.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.81).

BP6

Variant 7-151003858-C-A is Benign according to our data. Variant chr7-151003858-C-A is described in ClinVar as Benign. ClinVar VariationId is 1227867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000484524.5. 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+1554C>A	intron	N/A	NP_000594.2
NOS3	NM_001160111.1		c.*570C>A	3_prime_UTR	Exon 14 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.*455C>A	3_prime_UTR	Exon 14 of 14	NP_001153582.1	P29474-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000484524.5	TSL:1	c.*570C>A	3_prime_UTR	Exon 14 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.*455C>A	3_prime_UTR	Exon 14 of 14	ENSP00000420551.1	P29474-3
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1752+1554C>A	intron	N/A	ENSP00000297494.3	P29474-1

Frequencies

GnomAD3 genomes

AF:

0.0684

AC:

10400

AN:

151996

Hom.:

492

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0512

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.0719

Gnomad SAS

AF:

0.0625

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0954

Gnomad OTH

AF:

0.0507

GnomAD4 exome

AF:

0.0825

AC:

20166

AN:

244366

Hom.:

946

Cov.:

AF XY:

0.0821

AC XY:

11088

AN XY:

135092

show subpopulations

African (AFR)

AF:

0.0167

AC:

120

AN:

7192

American (AMR)

AF:

0.0492

AC:

1051

AN:

21382

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

100

AN:

7048

East Asian (EAS)

AF:

0.0717

AC:

611

AN:

8516

South Asian (SAS)

AF:

0.0750

AC:

3658

AN:

48782

European-Finnish (FIN)

AF:

0.132

AC:

1724

AN:

13084

Middle Eastern (MID)

AF:

0.0648

AC:

AN:

1234

European-Non Finnish (NFE)

AF:

0.0953

AC:

11965

AN:

125546

Other (OTH)

AF:

0.0740

AC:

857

AN:

11582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

907

1814

2721

3628

4535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0683

AC:

10393

AN:

152114

Hom.:

491

Cov.:

AF XY:

0.0703

AC XY:

5227

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0174

AC:

722

AN:

41490

American (AMR)

AF:

0.0510

AC:

780

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.0717

AC:

372

AN:

5188

South Asian (SAS)

AF:

0.0623

AC:

300

AN:

4814

European-Finnish (FIN)

AF:

0.141

AC:

1490

AN:

10560

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0954

AC:

6489

AN:

67992

Other (OTH)

AF:

0.0497

AC:

105

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

492

984

1477

1969

2461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0800

Hom.:

1207

Bravo

AF:

0.0583

Asia WGS

AF:

0.0620

AC:

216

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.6

(source)

DANN

Benign

0.72

PhyloP100

0.97

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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