rs3917518

Variant names:

• chr7-95312469-C-A
• rs3917518
• NM_000446.7:c.371-892G>T

Variant summary

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

The NM_000446.7(PON1):​c.371-892G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 152,236 control chromosomes in the GnomAD database, including 768 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 0.088 (768 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.371-892G>T		intron_variant	Intron 4 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.371-892G>T		intron_variant	Intron 4 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*96-892G>T		intron_variant	Intron 4 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.491-892G>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13420 AN: 152118 Hom.: 765 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.0799

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

GnomAD4 genome AF: 0.0883 AC: 13439 AN: 152236 Hom.: 768 Cov.: 33 AF XY: 0.0888 AC XY: 6610 AN XY: 74446

African (AFR) AF: 0.142 AC: 5890 AN: 41524

American (AMR) AF: 0.122 AC: 1872 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.119 AC: 616 AN: 5180

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4828

European-Finnish (FIN) AF: 0.0692 AC: 734 AN: 10604

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0521 AC: 3543 AN: 68022

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0727 Hom.: 75

Bravo AF: 0.0970

Asia WGS AF: 0.0990 AC: 344 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.72
PhyloP100		-0.35
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: rs3917518; hg19: chr7-94941781;