Genetic Variant PON1:c.146-154C>A (chr7-95316943-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000446.7(PON1):c.146-154C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 151,974 control chromosomes in the GnomAD database, including 12,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12467 hom., cov: 33)

Consequence

PON1
NM_000446.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.997

Publications

14 publications found

Variant links:

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

PON1 Gene-Disease associations (from GenCC):

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

PON1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 7-95316943-G-T is Benign according to our data. Variant chr7-95316943-G-T is described in ClinVar as Benign. ClinVar VariationId is 1225160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. 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
	PON1	NM_000446.7	MANE Select	c.146-154C>A		intron	N/A	NP_000437.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PON1	ENST00000222381.8	TSL:1 MANE Select	c.146-154C>A	intron	N/A	ENSP00000222381.3	P27169
PON1	ENST00000893040.1		c.146-154C>A	intron	N/A	ENSP00000563099.1
PON1	ENST00000893036.1		c.146-154C>A	intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60268

AN:

151856

Hom.:

12434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.478

Gnomad AMI

AF:

0.359

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.351

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.398

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.334

Gnomad OTH

AF:

0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.397

AC:

60349

AN:

151974

Hom.:

12467

Cov.:

AF XY:

0.399

AC XY:

29638

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.478

AC:

19800

AN:

41432

American (AMR)

AF:

0.432

AC:

6605

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.351

AC:

1216

AN:

3468

East Asian (EAS)

AF:

0.646

AC:

3338

AN:

5164

South Asian (SAS)

AF:

0.397

AC:

1917

AN:

4826

European-Finnish (FIN)

AF:

0.334

AC:

3514

AN:

10536

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.334

AC:

22692

AN:

67956

Other (OTH)

AF:

0.402

AC:

848

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1923

3846

5768

7691

9614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<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:

0.357

Hom.:

7948

Bravo

AF:

0.413

Asia WGS

AF:

0.541

AC:

1878

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.79

(source)

DANN

Benign

0.52

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over