chr7-95298028-CCTTT-C

Variant names:

• chr7-95298028-CCTTT-C
• rs3832528
• NM_000446.7:c.*912_*915delAAAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000446.7(PON1):​c.*912_*915delAAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 151,986 control chromosomes in the GnomAD database, including 845 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.096 (845 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PON1 NM_000446.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 2 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.*912_*915delAAAG		3_prime_UTR_variant	Exon 9 of 9	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.*912_*915delAAAG		3_prime_UTR_variant	Exon 9 of 9	1	NM_000446.7	ENSP00000222381.3

Frequencies

GnomAD3 genomes AF: 0.0963 AC: 14624 AN: 151868 Hom.: 842 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0883

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0963 AC: 14642 AN: 151986 Hom.: 845 Cov.: 31 AF XY: 0.0997 AC XY: 7404 AN XY: 74288

African (AFR) AF: 0.141 AC: 5842 AN: 41422

American (AMR) AF: 0.136 AC: 2072 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3466

East Asian (EAS) AF: 0.135 AC: 698 AN: 5164

South Asian (SAS) AF: 0.0990 AC: 476 AN: 4810

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10564

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3863 AN: 67980

Other (OTH) AF: 0.0874 AC: 184 AN: 2106

Alfa AF: 0.0775 Hom.: 71

Bravo AF: 0.103

Asia WGS AF: 0.106 AC: 368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
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: rs3832528; hg19: chr7-94927340;