rs2272365

Variant names:

• chr7-95319314-A-C
• rs2272365
• NM_000446.7:c.75-921T>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.75-921T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,042 control chromosomes in the GnomAD database, including 1,715 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 0.13 (1715 hom., cov: 30)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 12 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-921T>G		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.75-921T>G		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.75-921T>G		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19018 AN: 151924 Hom.: 1720 Cov.: 30

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0885

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.125 AC: 19015 AN: 152042 Hom.: 1715 Cov.: 30 AF XY: 0.127 AC XY: 9428 AN XY: 74270

African (AFR) AF: 0.0302 AC: 1253 AN: 41520

American (AMR) AF: 0.158 AC: 2416 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3470

East Asian (EAS) AF: 0.428 AC: 2197 AN: 5134

South Asian (SAS) AF: 0.177 AC: 850 AN: 4798

European-Finnish (FIN) AF: 0.0885 AC: 936 AN: 10572

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10287 AN: 67954

Other (OTH) AF: 0.150 AC: 318 AN: 2114

Alfa AF: 0.150 Hom.: 3084

Bravo AF: 0.129

Asia WGS AF: 0.288 AC: 1000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.60
PhyloP100		1.0
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: rs2272365; hg19: chr7-94948626;