rs147006695

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_000940.3(PON3):c.94C>T(p.Arg32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 0 hom. )

Consequence

PON3
NM_000940.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.39

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 links:

PON3 (HGNC:):

PON3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 7-95394695-G-A is Benign according to our data. Variant chr7-95394695-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488870.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON3	NM_000940.3 linkuse as main transcript	c.94C>T	p.Arg32*	stop_gained	2/9	ENST00000265627.10	NP_000931.1	Q15166

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10 linkuse as main transcript	c.94C>T	p.Arg32*	stop_gained	2/9	1	NM_000940.3	ENSP00000265627.5		Q15166

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

291

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00151

AC:

380

AN:

251486

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00215

AC:

3139

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1518

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.00259

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00191

AC:

291

AN:

152248

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00318

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	The R32X variant in the PON3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The NHLBI ESP Exome Sequencing Project reports R32X was observed in 19/8600 alleles from individuals of European American background, indicating it may be a rare variant in this population; no individuals homozygous for this allele were reported in this control population. We interpret R32X as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Amyotrophic lateral sclerosis

Benign:1

Likely benign, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

-0.0040

FATHMM_MKL

Benign

0.088

Vest4

0.78

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.34

Position offset: 19

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