Genetic Variant PON3:c.-31C>T (chr7-95396381-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000902748.1(PON3):c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,608,114 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 29 hom., cov: 31)

Exomes 𝑓: 0.015 ( 273 hom. )

Consequence

PON3
ENST00000902748.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0500

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PON3 links:

ENSG00000233942 (HGNC:):

ENSG00000233942 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0113 (1724/152114) while in subpopulation SAS AF = 0.0475 (229/4816). AF 95% confidence interval is 0.0425. There are 29 homozygotes in GnomAd4. There are 861 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1724 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000902748.1. 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.-31C>T		upstream_gene	N/A	NP_000931.1	Q15166

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
PON3	ENST00000902748.1	c.-31C>T	5_prime_UTR	Exon 1 of 10	ENSP00000572807.1
PON3	ENST00000902749.1	c.-31C>T	5_prime_UTR	Exon 1 of 10	ENSP00000572808.1
PON3	ENST00000902752.1	c.-31C>T	5_prime_UTR	Exon 1 of 10	ENSP00000572811.1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1718

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0277

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0163

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0196

AC:

4820

AN:

245410

AF XY:

0.0201

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.0430

Gnomad ASJ exome

AF:

0.00673

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.00540

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.0151

AC:

21934

AN:

1456000

Hom.:

273

Cov.:

AF XY:

0.0157

AC XY:

11395

AN XY:

724626

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

33322

American (AMR)

AF:

0.0412

AC:

1838

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00614

AC:

160

AN:

26042

East Asian (EAS)

AF:

0.0157

AC:

623

AN:

39624

South Asian (SAS)

AF:

0.0458

AC:

3942

AN:

86138

European-Finnish (FIN)

AF:

0.00592

AC:

314

AN:

53038

Middle Eastern (MID)

AF:

0.00626

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0127

AC:

14038

AN:

1107320

Other (OTH)

AF:

0.0152

AC:

914

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1196

2392

3588

4784

5980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0113

AC:

1724

AN:

152114

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

861

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41518

American (AMR)

AF:

0.0282

AC:

431

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0163

AC:

AN:

5140

South Asian (SAS)

AF:

0.0475

AC:

229

AN:

4816

European-Finnish (FIN)

AF:

0.00650

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0109

AC:

740

AN:

67952

Other (OTH)

AF:

0.0118

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0139

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.0290

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.9

(source)

DANN

Benign

0.86

PhyloP100

0.050

PromoterAI

-0.066

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over