7-95316062-T-C

Variant names:

• chr7-95316062-T-C
• rs854558
• NM_000446.7:c.202-572A>G

Variant summary

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

The ENST00000222381.8(PON1):​c.202-572A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 152,128 control chromosomes in the GnomAD database, including 35,793 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 0.69 (35793 hom., cov: 33)
• Consequence: PON1 ENST00000222381.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000222381.8. 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.202-572A>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.202-572A>G		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.202-613A>G		intron	N/A	ENSP00000407359.1
	PON1	ENST00000470502.1	TSL:4	n.322-572A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104128 AN: 152010 Hom.: 35756 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.715

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

GnomAD4 genome AF: 0.685 AC: 104222 AN: 152128 Hom.: 35793 Cov.: 33 AF XY: 0.684 AC XY: 50847 AN XY: 74370

African (AFR) AF: 0.655 AC: 27176 AN: 41476

American (AMR) AF: 0.706 AC: 10798 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2594 AN: 3472

East Asian (EAS) AF: 0.683 AC: 3529 AN: 5168

South Asian (SAS) AF: 0.600 AC: 2888 AN: 4814

European-Finnish (FIN) AF: 0.683 AC: 7225 AN: 10582

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47635 AN: 68008

Other (OTH) AF: 0.718 AC: 1516 AN: 2112

Alfa AF: 0.702 Hom.: 52995

Bravo AF: 0.691

Asia WGS AF: 0.660 AC: 2297 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	5.8
DANN	Benign	0.44
PhyloP100		0.042
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: rs854558; hg19: chr7-94945374;