7-95318716-T-C

Position:

• chr7-95318716-T-C

Variant summary

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

The NM_000446.7(PON1):​c.75-323A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0754 in 280,878 control chromosomes in the GnomAD database, including 1,051 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 0.084 (674 hom., cov: 32)
  • Exomes 𝑓: 0.065 (377 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216

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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-323A>G		intron_variant		ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.75-323A>G		intron_variant		1	NM_000446.7	ENSP00000222381	P1
PON1	ENST00000433729.1	c.75-323A>G		intron_variant, NMD_transcript_variant		3		ENSP00000407359

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12766 AN: 152098 Hom.: 672 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0750

GnomAD4 exome AF: 0.0652 AC: 8392 AN: 128662 Hom.: 377 AF XY: 0.0653 AC XY: 4467 AN XY: 68454

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.0635

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0641

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0840 AC: 12784 AN: 152216 Hom.: 674 Cov.: 32 AF XY: 0.0844 AC XY: 6282 AN XY: 74432

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0643

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0725

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.0524

Gnomad4 OTH AF: 0.0742

Alfa AF: 0.0541 Hom.: 257

Bravo AF: 0.0917

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.71

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: rs3917493; hg19: chr7-94948028;