NM_000940.3:c.496G>A

Variant names:

• chr7-95364062-C-T
• rs201544566
• NM_000940.3:c.496G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 15/23 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:3
• Conservation: PhyloP100: 1.42
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041158378).
• BS2: High AC in GnomAd4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000940.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	NM_000940.3	MANE Select	c.496G>A	p.Val166Met	missense splice_region	Exon 6 of 9	NP_000931.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.496G>A	p.Val166Met	missense splice_region	Exon 6 of 9	ENSP00000265627.5
	PON3	ENST00000902762.1		c.679G>A	p.Val227Met	missense splice_region	Exon 7 of 10	ENSP00000572821.1
	PON3	ENST00000902763.1		c.649G>A	p.Val217Met	missense splice_region	Exon 7 of 10	ENSP00000572822.1

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

GnomAD2 exomes AF: 0.000696 AC: 174 AN: 250066 AF XY: 0.000725

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 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

African (AFR) AF: 0.000717 AC: 24 AN: 33458

American (AMR) AF: 0.00145 AC: 65 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5764

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111392

Other (OTH) AF: 0.00126 AC: 76 AN: 60370

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000709 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.099
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.4
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.032	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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs201544566; hg19: chr7-94993374;