rs3917477

Positions:

• chr7-95322654-A-G

Variant summary

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

The NM_000446.7(PON1):​c.74+1748T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 152,248 control chromosomes in the GnomAD database, including 622 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 0.074 (622 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.56

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PON1	NM_000446.7	c.74+1748T>C		intron_variant		ENST00000222381.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PON1	ENST00000222381.8	c.74+1748T>C		intron_variant		1	NM_000446.7	P1
PON1	ENST00000433729.1	c.74+1748T>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11179 AN: 152130 Hom.: 617 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0598

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

GnomAD4 genome AF: 0.0736 AC: 11201 AN: 152248 Hom.: 622 Cov.: 31 AF XY: 0.0739 AC XY: 5503 AN XY: 74440

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0332

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0410 Hom.: 311

Bravo AF: 0.0840

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.79

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: rs3917477; hg19: chr7-94951966;