rs705378

Positions:

• chr7-95317259-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.146-470C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 151,986 control chromosomes in the GnomAD database, including 7,012 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 0.29 (7012 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON1	NM_000446.7	c.146-470C>A		intron_variant		ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.146-470C>A		intron_variant		1	NM_000446.7	ENSP00000222381	P1
PON1	ENST00000433729.1	c.146-470C>A		intron_variant, NMD_transcript_variant		3		ENSP00000407359
PON1	ENST00000470502.1	n.266-470C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43615 AN: 151866 Hom.: 7010 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.287 AC: 43626 AN: 151986 Hom.: 7012 Cov.: 32 AF XY: 0.284 AC XY: 21057 AN XY: 74274

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.0359

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.316

Alfa AF: 0.313 Hom.: 1102

Bravo AF: 0.277

Asia WGS AF: 0.116 AC: 403 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.0
DANN	Benign	0.55

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

Other links and lift over

dbSNP: rs705378; hg19: chr7-94946571;