7-95298612-C-T

Variant names:

• chr7-95298612-C-T
• rs854552
• NM_000446.7:c.*332G>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.*332G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 385,974 control chromosomes in the GnomAD database, including 96,441 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 0.65 (33094 hom., cov: 31)
  • Exomes 𝑓: 0.73 (63347 hom.)
• Consequence: PON1 NM_000446.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 26 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 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.*332G>A		3_prime_UTR	Exon 9 of 9	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.*332G>A		3_prime_UTR	Exon 9 of 9	ENSP00000222381.3
	PON1	ENST00000462594.1	TSL:2	n.*137G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98112 AN: 151862 Hom.: 33099 Cov.: 31

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.696

GnomAD4 exome AF: 0.732 AC: 171203 AN: 233994 Hom.: 63347 Cov.: 2 AF XY: 0.737 AC XY: 93577 AN XY: 126966

African (AFR) AF: 0.437 AC: 2947 AN: 6748

American (AMR) AF: 0.679 AC: 8230 AN: 12126

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 4705 AN: 6054

East Asian (EAS) AF: 0.777 AC: 8438 AN: 10860

South Asian (SAS) AF: 0.773 AC: 31597 AN: 40862

European-Finnish (FIN) AF: 0.665 AC: 6948 AN: 10454

Middle Eastern (MID) AF: 0.778 AC: 678 AN: 872

European-Non Finnish (NFE) AF: 0.739 AC: 98956 AN: 133910

Other (OTH) AF: 0.719 AC: 8704 AN: 12108

GnomAD4 genome AF: 0.646 AC: 98133 AN: 151980 Hom.: 33094 Cov.: 31 AF XY: 0.647 AC XY: 48075 AN XY: 74274

African (AFR) AF: 0.436 AC: 18051 AN: 41398

American (AMR) AF: 0.691 AC: 10557 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2726 AN: 3470

East Asian (EAS) AF: 0.771 AC: 3969 AN: 5150

South Asian (SAS) AF: 0.768 AC: 3705 AN: 4822

European-Finnish (FIN) AF: 0.637 AC: 6725 AN: 10556

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50101 AN: 67988

Other (OTH) AF: 0.692 AC: 1462 AN: 2112

Alfa AF: 0.712 Hom.: 149352

Bravo AF: 0.638

Asia WGS AF: 0.728 AC: 2530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.1
DANN	Benign	0.44
PhyloP100		0.18
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: rs854552; hg19: chr7-94927924;