rs2237584

Variant names:

• chr7-95321525-C-T
• rs2237584
• NM_000446.7:c.74+2877G>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.74+2877G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 152,210 control chromosomes in the GnomAD database, including 635 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 0.070 (635 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 7 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.74+2877G>A		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+2877G>A		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.74+2877G>A		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.0701 AC: 10664 AN: 152092 Hom.: 635 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0617

Gnomad OTH AF: 0.0809

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

GnomAD4 genome AF: 0.0701 AC: 10672 AN: 152210 Hom.: 635 Cov.: 32 AF XY: 0.0752 AC XY: 5596 AN XY: 74422

African (AFR) AF: 0.0204 AC: 848 AN: 41548

American (AMR) AF: 0.165 AC: 2516 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3472

East Asian (EAS) AF: 0.271 AC: 1399 AN: 5162

South Asian (SAS) AF: 0.120 AC: 579 AN: 4816

European-Finnish (FIN) AF: 0.0632 AC: 671 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0617 AC: 4197 AN: 68004

Other (OTH) AF: 0.0829 AC: 175 AN: 2112

Alfa AF: 0.0710 Hom.: 928

Bravo AF: 0.0768

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.67
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: rs2237584; hg19: chr7-94950837;