Genetic Variant PON3:p.Ala99Ala (chr7-95372243-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000940.3(PON3):c.297G>A(p.Ala99Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,612,772 control chromosomes in the GnomAD database, including 218,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22797 hom., cov: 32)

Exomes 𝑓: 0.51 ( 195610 hom. )

Consequence

PON3
NM_000940.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0810

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 7-95372243-C-T is Benign according to our data. Variant chr7-95372243-C-T is described in ClinVar as [Benign]. Clinvar id is 1289181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.081 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3 link	c.297G>A	p.Ala99Ala	synonymous_variant	Exon 4 of 9	ENST00000265627.10	NP_000931.1	Q15166

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10 link	c.297G>A	p.Ala99Ala	synonymous_variant	Exon 4 of 9	1	NM_000940.3	ENSP00000265627.5		Q15166

Frequencies

GnomAD3 genomes

AF:

0.541

AC:

82082

AN:

151792

Hom.:

22743

Cov.:

show subpopulations

Gnomad AFR

AF:

0.572

Gnomad AMI

AF:

0.618

Gnomad AMR

AF:

0.613

Gnomad ASJ

AF:

0.418

Gnomad EAS

AF:

0.782

Gnomad SAS

AF:

0.690

Gnomad FIN

AF:

0.627

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.516

GnomAD3 exomes

AF:

0.571

AC:

143582

AN:

251258

Hom.:

43001

AF XY:

0.569

AC XY:

77217

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.580

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.786

Gnomad SAS exome

AF:

0.683

Gnomad FIN exome

AF:

0.607

Gnomad NFE exome

AF:

0.473

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.509

AC:

744296

AN:

1460862

Hom.:

195610

Cov.:

AF XY:

0.513

AC XY:

372834

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.585

Gnomad4 AMR exome

AF:

0.698

Gnomad4 ASJ exome

AF:

0.407

Gnomad4 EAS exome

AF:

0.821

Gnomad4 SAS exome

AF:

0.677

Gnomad4 FIN exome

AF:

0.602

Gnomad4 NFE exome

AF:

0.473

Gnomad4 OTH exome

AF:

0.519

GnomAD4 genome

AF:

0.541

AC:

82194

AN:

151910

Hom.:

22797

Cov.:

AF XY:

0.555

AC XY:

41207

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.573

Gnomad4 AMR

AF:

0.613

Gnomad4 ASJ

AF:

0.418

Gnomad4 EAS

AF:

0.782

Gnomad4 SAS

AF:

0.690

Gnomad4 FIN

AF:

0.627

Gnomad4 NFE

AF:

0.470

Gnomad4 OTH

AF:

0.521

Alfa

AF:

0.486

Hom.:

43724

Bravo

AF:

0.541

Asia WGS

AF:

0.737

AC:

2561

AN:

3476

EpiCase

AF:

0.464

EpiControl

AF:

0.468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

4.5

DANN

Benign

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over