rs3917493

Variant names:

• chr7-95318716-T-C
• rs3917493
• NM_000446.7:c.75-323A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-95318716-T-C
• chr7-95318716-T-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.75-323A>G		intron	N/A	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.75-323A>G		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.75-323A>G		intron	N/A	ENSP00000407359.1
	PON1	ENST00000470502.1	TSL:4	n.-129A>G		upstream_gene	N/A

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

African (AFR) AF: 0.114 AC: 495 AN: 4332

American (AMR) AF: 0.159 AC: 997 AN: 6260

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 222 AN: 3496

East Asian (EAS) AF: 0.115 AC: 878 AN: 7664

South Asian (SAS) AF: 0.0618 AC: 1070 AN: 17318

European-Finnish (FIN) AF: 0.0641 AC: 340 AN: 5302

Middle Eastern (MID) AF: 0.0667 AC: 34 AN: 510

European-Non Finnish (NFE) AF: 0.0506 AC: 3886 AN: 76790

Other (OTH) AF: 0.0672 AC: 470 AN: 6990

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

African (AFR) AF: 0.127 AC: 5260 AN: 41534

American (AMR) AF: 0.120 AC: 1833 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3470

East Asian (EAS) AF: 0.120 AC: 622 AN: 5174

South Asian (SAS) AF: 0.0725 AC: 349 AN: 4816

European-Finnish (FIN) AF: 0.0688 AC: 730 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0524 AC: 3563 AN: 68012

Other (OTH) AF: 0.0742 AC: 157 AN: 2116

Alfa AF: 0.0606 Hom.: 451

Bravo AF: 0.0917

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.71
PhyloP100		0.22
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: rs3917493; hg19: chr7-94948028;