Genetic Variant PON3:p.Val126Val (chr7-95367478-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000940.3(PON3):c.378G>A(p.Val126Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,612,930 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.036 ( 328 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 315 hom. )

Consequence

PON3
NM_000940.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0980

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP7

Synonymous conserved (PhyloP=0.098 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3 link	c.378G>A	p.Val126Val	synonymous_variant	Exon 5 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.378G>A	p.Val126Val	synonymous_variant	Exon 5 of 9	1	NM_000940.3	ENSP00000265627.5		Q15166

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5472

AN:

152108

Hom.:

326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.00982

AC:

2465

AN:

251054

AF XY:

0.00716

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00764

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000599

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00416

AC:

6078

AN:

1460704

Hom.:

315

Cov.:

AF XY:

0.00368

AC XY:

2673

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.130

AC:

4322

AN:

33360

American (AMR)

AF:

0.00888

AC:

397

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000301

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00888

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.000678

AC:

754

AN:

1111336

Other (OTH)

AF:

0.00868

AC:

524

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

266

532

799

1065

1331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.0360

AC:

5485

AN:

152226

Hom.:

328

Cov.:

AF XY:

0.0351

AC XY:

2612

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.124

AC:

5168

AN:

41512

American (AMR)

AF:

0.0141

AC:

215

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68006

Other (OTH)

AF:

0.0232

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

242

483

725

966

1208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0135

Hom.:

303

Bravo

AF:

0.0410

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.3

(source)

DANN

Benign

0.58

PhyloP100

0.098

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Computational scores

Splicing

Publications

Other links and lift over