rs2299257

Positions:

• chr7-95313453-A-C
• chr7-95313453-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.370+1869T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,054 control chromosomes in the GnomAD database, including 16,193 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 0.45 (16193 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON1	NM_000446.7	c.370+1869T>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.370+1869T>G		intron_variant		1	NM_000446.7	ENSP00000222381	P1
PON1	ENST00000433729.1	c.*95+1869T>G		intron_variant, NMD_transcript_variant		3		ENSP00000407359
PON1	ENST00000470502.1	n.490+1869T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68360 AN: 151934 Hom.: 16154 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.450 AC: 68456 AN: 152054 Hom.: 16193 Cov.: 32 AF XY: 0.450 AC XY: 33449 AN XY: 74304

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.442

Alfa AF: 0.396 Hom.: 12444

Bravo AF: 0.468

Asia WGS AF: 0.549 AC: 1908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	11
DANN	Benign	0.69

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: rs2299257; hg19: chr7-94942765;