Genetic Variant PON3:c.*27_*29dupAAA (chr7-95359943-C-CTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000940.3(PON3):c.*27_*29dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,464,800 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

PON3
NM_000940.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.382

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 45 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.27_29dupAAA		3_prime_UTR	Exon 9 of 9	NP_000931.1	Q15166

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PON3	ENST00000265627.10	TSL:1 MANE Select	c.27_29dupAAA	3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
PON3	ENST00000427422.5	TSL:3	c.143_145dupAAA	splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
PON3	ENST00000902762.1		c.27_29dupAAA	3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes

AF:

0.000325

AC:

AN:

138340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000732

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00602

Gnomad SAS

AF:

0.000232

Gnomad FIN

AF:

0.000245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000317

Gnomad OTH

AF:

0.000535

GnomAD2 exomes

AF:

0.00105

AC:

135

AN:

129166

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.00244

Gnomad AMR exome

AF:

0.000399

Gnomad ASJ exome

AF:

0.000535

Gnomad EAS exome

AF:

0.00331

Gnomad FIN exome

AF:

0.00160

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000283

AC:

376

AN:

1326434

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

207

AN XY:

662806

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00152

AC:

AN:

28878

American (AMR)

AF:

0.000502

AC:

AN:

37812

Ashkenazi Jewish (ASJ)

AF:

0.000164

AC:

AN:

24382

East Asian (EAS)

AF:

0.00155

AC:

AN:

37434

South Asian (SAS)

AF:

0.000689

AC:

AN:

76956

European-Finnish (FIN)

AF:

0.000414

AC:

AN:

43446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.000156

AC:

159

AN:

1016832

Other (OTH)

AF:

0.000378

AC:

AN:

55540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.339

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000325

AC:

AN:

138366

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

66852

show subpopulations

African (AFR)

AF:

0.000237

AC:

AN:

38024

American (AMR)

AF:

0.0000732

AC:

AN:

13668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3242

East Asian (EAS)

AF:

0.00603

AC:

AN:

4808

South Asian (SAS)

AF:

0.000233

AC:

AN:

4294

European-Finnish (FIN)

AF:

0.000245

AC:

AN:

8166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000317

AC:

AN:

63168

Other (OTH)

AF:

0.000534

AC:

AN:

1874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000339

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.38

Splicing

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

Publications

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7-95359943-CTTTTTT-CTTTTTTTTT

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