7-95308945-A-G

Variant names:

• chr7-95308945-A-G
• rs2057681
• NM_000446.7:c.498-734T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.498-734T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 151,596 control chromosomes in the GnomAD database, including 16,405 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 0.43 (16405 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.918
• Publications: 18 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=-0.5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.498-734T>C		intron_variant	Intron 5 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.498-734T>C		intron_variant	Intron 5 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*223-734T>C		intron_variant	Intron 5 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64847 AN: 151476 Hom.: 16357 Cov.: 31

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.429 AC: 64959 AN: 151596 Hom.: 16405 Cov.: 31 AF XY: 0.429 AC XY: 31783 AN XY: 74026

African (AFR) AF: 0.694 AC: 28702 AN: 41366

American (AMR) AF: 0.426 AC: 6491 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1118 AN: 3470

East Asian (EAS) AF: 0.642 AC: 3299 AN: 5138

South Asian (SAS) AF: 0.391 AC: 1876 AN: 4802

European-Finnish (FIN) AF: 0.296 AC: 3082 AN: 10418

Middle Eastern (MID) AF: 0.340 AC: 98 AN: 288

European-Non Finnish (NFE) AF: 0.282 AC: 19125 AN: 67870

Other (OTH) AF: 0.411 AC: 865 AN: 2106

Alfa AF: 0.335 Hom.: 40487

Bravo AF: 0.453

Asia WGS AF: 0.546 AC: 1897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.71
PhyloP100		0.92
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: rs2057681; hg19: chr7-94938257;