chr7-95308134-T-C

Position:

chr7-95308134-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000222381.8(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. 14/20 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
ENST00000222381.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.954

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PON1	NM_000446.7 linkuse as main transcript	c.575A>G	p.Gln192Arg	missense_variant	6/9	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8 linkuse as main transcript	c.575A>G	p.Gln192Arg	missense_variant	6/9	1	NM_000446.7	ENSP00000222381	P1
PON1	ENST00000433729.1 linkuse as main transcript	c.*300A>G		3_prime_UTR_variant, NMD_transcript_variant	6/9	3		ENSP00000407359

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

GnomAD3 exomes

AF:

0.378

AC:

95101

AN:

251302

Hom.:

20638

AF XY:

0.365

AC XY:

49574

AN XY:

135812

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 SAS exome

AF:

0.382

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

Gnomad4 AFR exome

AF:

0.684

Gnomad4 AMR exome

AF:

0.487

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.657

Gnomad4 SAS exome

AF:

0.375

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.286

Gnomad4 OTH exome

AF:

0.342

GnomAD4 genome

AF:

0.421

AC:

63977

AN:

151892

Hom.:

15757

Cov.:

AF XY:

0.422

AC XY:

31335

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.670

Gnomad4 AMR

AF:

0.424

Gnomad4 ASJ

AF:

0.322

Gnomad4 EAS

AF:

0.642

Gnomad4 SAS

AF:

0.389

Gnomad4 FIN

AF:

0.293

Gnomad4 NFE

AF:

0.281

Gnomad4 OTH

AF:

0.407

Alfa

AF:

0.319

Hom.:

20890

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2019	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) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PON1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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

association, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

Coronary artery disease, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

Coronary artery spasm 2, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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