7-95316772-A-T

Position:

chr7-95316772-A-T

Variant summary

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

The ENST00000222381.8(PON1):c.163T>A(p.Leu55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,611,280 control chromosomes in the GnomAD database, including 93,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7008 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86372 hom. )

Consequence

PON1
ENST00000222381.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.197

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=0.0028376877).

BP6

Variant 7-95316772-A-T is Benign according to our data. Variant chr7-95316772-A-T is described in ClinVar as [Benign]. Clinvar id is 13736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 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.163T>A	p.Leu55Met	missense_variant	3/9	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PON1	ENST00000222381.8 linkuse as main transcript	c.163T>A	p.Leu55Met	missense_variant	3/9	1	NM_000446.7	ENSP00000222381	P1
PON1	ENST00000470502.1 linkuse as main transcript	n.283T>A		non_coding_transcript_exon_variant	2/4	4
PON1	ENST00000433729.1 linkuse as main transcript	c.163T>A	p.Leu55Met	missense_variant, NMD_transcript_variant	3/9	3		ENSP00000407359

Frequencies

GnomAD3 genomes

AF:

0.287

AC:

43605

AN:

151866

Hom.:

7006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.0357

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.318

GnomAD3 exomes

AF:

0.289

AC:

72592

AN:

251376

Hom.:

12116

AF XY:

0.294

AC XY:

39957

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.200

Gnomad ASJ exome

AF:

0.407

Gnomad EAS exome

AF:

0.0347

Gnomad SAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.335

AC:

488902

AN:

1459296

Hom.:

86372

Cov.:

AF XY:

0.333

AC XY:

241873

AN XY:

726094

show subpopulations

Gnomad4 AFR exome

AF:

0.168

Gnomad4 AMR exome

AF:

0.209

Gnomad4 ASJ exome

AF:

0.400

Gnomad4 EAS exome

AF:

0.0589

Gnomad4 SAS exome

AF:

0.210

Gnomad4 FIN exome

AF:

0.361

Gnomad4 NFE exome

AF:

0.362

Gnomad4 OTH exome

AF:

0.323

GnomAD4 genome

AF:

0.287

AC:

43616

AN:

151984

Hom.:

7008

Cov.:

AF XY:

0.284

AC XY:

21050

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.273

Gnomad4 ASJ

AF:

0.397

Gnomad4 EAS

AF:

0.0360

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.351

Gnomad4 NFE

AF:

0.366

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.349

Hom.:

7322

Bravo

AF:

0.277

TwinsUK

AF:

0.369

AC:

1369

ALSPAC

AF:

0.363

AC:

1398

ESP6500AA

AF:

0.173

AC:

762

ESP6500EA

AF:

0.373

AC:

3208

ExAC

AF:

0.291

AC:

35356

Asia WGS

AF:

0.118

AC:

413

AN:

3478

EpiCase

AF:

0.368

EpiControl

AF:

0.366

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	Jun 09, 2021	This variant is associated with the following publications: (PMID: 23590198, 23538572, 26241956, 9011577, 21718208, 21231776, 20390392, 21229382, 12867538, 21783258, 20812194, 19269283, 18708400, 10952224, 20042177, 23007074) -
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 16, 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

- -

Microvascular complications of diabetes, susceptibility to, 5

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Coronary artery disease, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.50

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

REVEL

Benign

0.064

Sift

Uncertain

0.020

Sift4G

Uncertain

0.0030

Polyphen

0.0040

Vest4

0.11

MPC

0.16

ClinPred

0.041

GERP RS

-1.8

Varity_R

0.14

gMVP

0.81

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