NM_000446.7:c.575A>G

Variant names:

Variant summary

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

The NM_000446.7(PON1):c.575A>G(p.Gln192Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,428 control chromosomes in the GnomAD database, including 97,270 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 15757 hom., cov: 31)

Exomes 𝑓: 0.32 ( 81513 hom. )

Consequence

PON1
NM_000446.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.954

Publications

1187 publications found

Variant links:

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

PON1 Gene-Disease associations (from GenCC):

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

PON1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.7591353E-6).

BP6

Variant 7-95308134-T-C is Benign according to our data. Variant chr7-95308134-T-C is described in ClinVar as [Benign]. Clinvar id is 13735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7 link	c.575A>G	p.Gln192Arg	missense_variant	Exon 6 of 9	ENST00000222381.8	NP_000437.3	P27169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PON1	ENST00000222381.8 link	c.575A>G	p.Gln192Arg	missense_variant	Exon 6 of 9	1	NM_000446.7	ENSP00000222381.3	P27169
PON1	ENST00000433729.1 link	n.*300A>G		non_coding_transcript_exon_variant	Exon 6 of 9	3		ENSP00000407359.1	F8WF42
PON1	ENST00000433729.1 link	n.*300A>G		3_prime_UTR_variant	Exon 6 of 9	3		ENSP00000407359.1	F8WF42

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63871

AN:

151774

Hom.:

15712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.642

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.401

GnomAD2 exomes

AF:

0.378

AC:

95101

AN:

251302

AF XY:

0.365

show subpopulations

Gnomad AFR exome

AF:

0.679

Gnomad AMR exome

AF:

0.495

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.659

Gnomad FIN exome

AF:

0.277

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.319

AC:

466410

AN:

1461536

Hom.:

81513

Cov.:

AF XY:

0.318

AC XY:

231442

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.684

AC:

22895

AN:

33476

American (AMR)

AF:

0.487

AC:

21776

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8157

AN:

26130

East Asian (EAS)

AF:

0.657

AC:

26053

AN:

39684

South Asian (SAS)

AF:

0.375

AC:

32373

AN:

86246

European-Finnish (FIN)

AF:

0.275

AC:

14677

AN:

53410

Middle Eastern (MID)

AF:

0.305

AC:

1757

AN:

5768

European-Non Finnish (NFE)

AF:

0.286

AC:

318049

AN:

1111710

Other (OTH)

AF:

0.342

AC:

20673

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

18365

36731

55096

73462

91827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.421

AC:

63977

AN:

151892

Hom.:

15757

Cov.:

AF XY:

0.422

AC XY:

31335

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.670

AC:

27720

AN:

41358

American (AMR)

AF:

0.424

AC:

6467

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1119

AN:

3470

East Asian (EAS)

AF:

0.642

AC:

3317

AN:

5166

South Asian (SAS)

AF:

0.389

AC:

1874

AN:

4812

European-Finnish (FIN)

AF:

0.293

AC:

3091

AN:

10544

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19130

AN:

67960

Other (OTH)

AF:

0.407

AC:

859

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1651

3303

4954

6606

8257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.336

Hom.:

44475

Bravo

AF:

0.446

TwinsUK

AF:

0.279

AC:

1034

ALSPAC

AF:

0.290

AC:

1119

ESP6500AA

AF:

0.660

AC:

2910

ESP6500EA

AF:

0.285

AC:

2451

ExAC

AF:

0.377

AC:

45754

Asia WGS

AF:

0.545

AC:

1892

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.293

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

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 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26122242, 25935173, 29229890, 11810302, 25036896, 24206655, 23625196, 22971504, 29409844, 30903418, 23538572, 23590198, 23054002, 24433930, 22800774, 26241956, 25153516, 15050299, 20646512, 21718208, 16239632, 19280995, 8098250, 21573798, 21465165, 19357718, 16914770, 18349088, 21783258, 19578796, 22750797, 21078685, 22796398, 20833162, 19269283, 22368149, 18708400, 23917967, 19846948, 18952040, 21820612, 20042177, 23007074, 21982484) -

PON1-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Enzyme activity finding

Other:1

Jun 09, 2025

OMIM

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.023

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.023

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.053

MetaRNN

Benign

0.0000038

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.64

PhyloP100

-0.95

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

REVEL

Benign

0.024

Sift

Benign

0.78

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.010

MPC

0.16

ClinPred

0.0020

GERP RS

-1.0

Varity_R

0.031

gMVP

0.54

Mutation Taster

=99/1

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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NM_000446.7:c.575A>G

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