dbSNP rs13226149: PON3:p.Phe21Phe (chr7-95396288-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000940.3(PON3):c.63C>T(p.Phe21Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,292 control chromosomes in the GnomAD database, including 65,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7172 hom., cov: 30)

Exomes 𝑓: 0.28 ( 58097 hom. )

Consequence

PON3
NM_000940.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.77

Publications

36 publications found

Variant links:

Genes affected

PON3 (HGNC:9206): (paraoxonase 3) This gene is a member of the paraoxonase family and lies in a cluster on chromosome 7 with the other two family members. The encoded protein is secreted into the bloodstream and associates with high-density lipoprotein (HDL). The protein also rapidly hydrolyzes lactones and can inhibit the oxidation of low-density lipoprotein (LDL), a function that is believed to slow the initiation and progression of atherosclerosis. Alternatively spliced variants which encode different protein isoforms have been described; however, only one has been fully characterized. [provided by RefSeq, Jul 2008]

PON3 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PON3 links:

ENSG00000233942 (HGNC:):

ENSG00000233942 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 7-95396288-G-A is Benign according to our data. Variant chr7-95396288-G-A is described in ClinVar as [Benign]. Clinvar id is 1268453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.77 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3 link	c.63C>T	p.Phe21Phe	synonymous_variant	Exon 1 of 9	ENST00000265627.10	NP_000931.1	Q15166
LOC107986822	XR_001745283.2 link	n.-184G>A		upstream_gene_variant
LOC107986822	XR_007060439.1 link	n.-184G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10 link	c.63C>T	p.Phe21Phe	synonymous_variant	Exon 1 of 9	1	NM_000940.3	ENSP00000265627.5		Q15166

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45165

AN:

151612

Hom.:

7158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.341

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.465

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.287

AC:

71408

AN:

249158

AF XY:

0.293

show subpopulations

Gnomad AFR exome

AF:

0.353

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.185

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.277

AC:

404529

AN:

1461562

Hom.:

58097

Cov.:

AF XY:

0.280

AC XY:

203898

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.359

AC:

12011

AN:

33476

American (AMR)

AF:

0.222

AC:

9932

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4881

AN:

26128

East Asian (EAS)

AF:

0.195

AC:

7739

AN:

39700

South Asian (SAS)

AF:

0.388

AC:

33494

AN:

86250

European-Finnish (FIN)

AF:

0.440

AC:

23521

AN:

53416

Middle Eastern (MID)

AF:

0.253

AC:

1460

AN:

5768

European-Non Finnish (NFE)

AF:

0.265

AC:

294875

AN:

1111718

Other (OTH)

AF:

0.275

AC:

16616

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

16104

32208

48312

64416

80520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.298

AC:

45203

AN:

151730

Hom.:

7172

Cov.:

AF XY:

0.305

AC XY:

22651

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.341

AC:

14115

AN:

41394

American (AMR)

AF:

0.237

AC:

3619

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

669

AN:

3468

East Asian (EAS)

AF:

0.179

AC:

913

AN:

5104

South Asian (SAS)

AF:

0.381

AC:

1827

AN:

4794

European-Finnish (FIN)

AF:

0.465

AC:

4910

AN:

10554

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18087

AN:

67860

Other (OTH)

AF:

0.264

AC:

555

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1541

3082

4622

6163

7704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.266

Hom.:

17466

Bravo

AF:

0.278

Asia WGS

AF:

0.311

AC:

1080

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

- -

Jun 09, 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

-0.90

CADD

Benign

0.21

(source)

DANN

Benign

0.86

PhyloP100

-2.8

PromoterAI

-0.010

Neutral

(source)

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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rs13226149

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