rs854570

Variant names:

• chr7-95323380-C-A
• rs854570
• NM_000446.7:c.74+1022G>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.74+1022G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 152,024 control chromosomes in the GnomAD database, including 23,351 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 0.53 (23351 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.04
• Publications: 11 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.74+1022G>T		intron_variant	Intron 1 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.74+1022G>T		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.74+1022G>T		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80242 AN: 151906 Hom.: 23345 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.528 AC: 80280 AN: 152024 Hom.: 23351 Cov.: 32 AF XY: 0.534 AC XY: 39657 AN XY: 74310

African (AFR) AF: 0.265 AC: 10991 AN: 41442

American (AMR) AF: 0.617 AC: 9431 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2464 AN: 3470

East Asian (EAS) AF: 0.521 AC: 2692 AN: 5166

South Asian (SAS) AF: 0.548 AC: 2639 AN: 4818

European-Finnish (FIN) AF: 0.653 AC: 6883 AN: 10544

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.634 AC: 43068 AN: 67974

Other (OTH) AF: 0.594 AC: 1256 AN: 2114

Alfa AF: 0.580 Hom.: 45505

Bravo AF: 0.515

Asia WGS AF: 0.516 AC: 1798 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.027
DANN	Benign	0.42
PhyloP100		-3.0
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: rs854570; hg19: chr7-94952692;