rs201544566

chr7-95364062-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000940.3(PON3):c.496G>A(p.Val166Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,613,394 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: PON3 NM_000940.3 missense, splice_region
• Scores: Splicing: ADA: 0.00006258
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041158378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PON3	NM_000940.3	c.496G>A	p.Val166Met	missense_variant, splice_region_variant	6/9	ENST00000265627.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PON3	ENST00000265627.10	c.496G>A	p.Val166Met	missense_variant, splice_region_variant	6/9	1	NM_000940.3	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000696 AC: 174 AN: 250066 Hom.: 1 AF XY: 0.000725 AC XY: 98 AN XY: 135212

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.000426 AC: 622 AN: 1461144 Hom.: 5 Cov.: 30 AF XY: 0.000453 AC XY: 329 AN XY: 726906

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000268

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74448

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000752 Hom.: 1

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2017

The V166M variant in the PON3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V166M variant is observed in 26/11478 (0.2%) alleles from individuals of Latino background, and in 41/66332 (0.06%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The V166M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V166M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.062	T;.;T
Eigen	Benign	0.099
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.91	P;.;.
Vest4		0.56
MVP		0.55
MPC		0.25
ClinPred		0.067	T
GERP RS		2.5
Varity_R		0.25
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.010		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: rs201544566; hg19: chr7-94993374;