dbSNP rs854562: PON1:c.75-264G>A (chr7-95318657-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000446.7(PON1):c.75-264G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 396,058 control chromosomes in the GnomAD database, including 15,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5234 hom., cov: 32)

Exomes 𝑓: 0.28 ( 10655 hom. )

Consequence

PON1
NM_000446.7 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.209

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-95318657-C-T is Benign according to our data. Variant chr7-95318657-C-T is described in ClinVar as [Benign]. Clinvar id is 1284201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7 link	c.75-264G>A		intron_variant	Intron 1 of 8	ENST00000222381.8	NP_000437.3	P27169

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PON1	ENST00000222381.8 link	c.75-264G>A	intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3	P27169
PON1	ENST00000433729.1 link	n.75-264G>A	intron_variant	Intron 1 of 8	3		ENSP00000407359.1	F8WF42
PON1	ENST00000470502.1 link	n.-70G>A	upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35890

AN:

151926

Hom.:

5234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0840

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.394

Gnomad EAS

AF:

0.0351

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.312

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.323

Gnomad OTH

AF:

0.271

GnomAD4 exome

AF:

0.281

AC:

68649

AN:

244014

Hom.:

10655

AF XY:

0.277

AC XY:

36219

AN XY:

130798

show subpopulations

Gnomad4 AFR exome

AF:

0.0801

Gnomad4 AMR exome

AF:

0.215

Gnomad4 ASJ exome

AF:

0.401

Gnomad4 EAS exome

AF:

0.0533

Gnomad4 SAS exome

AF:

0.212

Gnomad4 FIN exome

AF:

0.320

Gnomad4 NFE exome

AF:

0.325

Gnomad4 OTH exome

AF:

0.294

GnomAD4 genome

AF:

0.236

AC:

35889

AN:

152044

Hom.:

5234

Cov.:

AF XY:

0.235

AC XY:

17433

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0838

Gnomad4 AMR

AF:

0.240

Gnomad4 ASJ

AF:

0.394

Gnomad4 EAS

AF:

0.0354

Gnomad4 SAS

AF:

0.199

Gnomad4 FIN

AF:

0.312

Gnomad4 NFE

AF:

0.323

Gnomad4 OTH

AF:

0.269

Alfa

AF:

0.310

Hom.:

9704

Bravo

AF:

0.224

Asia WGS

AF:

0.111

AC:

388

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.7

DANN

Benign

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over