rs3917532

Variant names:

• chr7-95310807-A-T
• rs3917532
• NM_000446.7:c.497+644T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.497+644T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,062 control chromosomes in the GnomAD database, including 15,740 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 0.42 (15740 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.544
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.497+644T>A		intron	N/A	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.497+644T>A		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.488+644T>A		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.497+644T>A		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63876 AN: 151944 Hom.: 15695 Cov.: 33

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.421 AC: 63982 AN: 152062 Hom.: 15740 Cov.: 33 AF XY: 0.421 AC XY: 31324 AN XY: 74342

African (AFR) AF: 0.670 AC: 27775 AN: 41460

American (AMR) AF: 0.421 AC: 6431 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3470

East Asian (EAS) AF: 0.640 AC: 3292 AN: 5144

South Asian (SAS) AF: 0.389 AC: 1877 AN: 4820

European-Finnish (FIN) AF: 0.293 AC: 3098 AN: 10582

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19130 AN: 67990

Other (OTH) AF: 0.406 AC: 858 AN: 2114

Alfa AF: 0.350 Hom.: 1363

Bravo AF: 0.445

Asia WGS AF: 0.544 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.35
DANN	Benign	0.63
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3917532; hg19: chr7-94940119;