7-95308134-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 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 NM_000446.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:3
• Conservation: PhyloP100: -0.954

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]

ACMG classification

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	UniProt
PON1	NM_000446.7	c.575A>G	p.Gln192Arg	missense_variant	6/9	ENST00000222381.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63871 AN: 151774 Hom.: 15712 Cov.: 31

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

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.: 37 AF XY: 0.318 AC XY: 231442 AN XY: 727070

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.: 31 AF XY: 0.422 AC XY: 31335 AN XY: 74250

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:2 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PON1-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

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) -

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	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.023
Dann	Benign	0.49
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.0000038	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.64	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.024
Sift	Benign	0.78	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.16
ClinPred		0.0020	T
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

Other links and lift over

dbSNP: rs662; hg19: chr7-94937446; COSMIC: COSV55931133; COSMIC: COSV55931133;