7-95317483-C-T

Variant names:

• chr7-95317483-C-T
• rs62467349
• NM_000446.7:c.146-694G>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.146-694G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 146,148 control chromosomes in the GnomAD database, including 1,110 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 0.12 (1110 hom., cov: 29)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 6 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.146-694G>A		intron_variant	Intron 2 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.146-694G>A		intron_variant	Intron 2 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.146-694G>A		intron_variant	Intron 2 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.266-694G>A		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.123 AC: 17979 AN: 146038 Hom.: 1108 Cov.: 29

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.0939

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.123 AC: 18001 AN: 146148 Hom.: 1110 Cov.: 29 AF XY: 0.125 AC XY: 8853 AN XY: 70762

African (AFR) AF: 0.106 AC: 4181 AN: 39286

American (AMR) AF: 0.126 AC: 1790 AN: 14262

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 288 AN: 3436

East Asian (EAS) AF: 0.0833 AC: 404 AN: 4848

South Asian (SAS) AF: 0.0936 AC: 430 AN: 4594

European-Finnish (FIN) AF: 0.189 AC: 1744 AN: 9238

Middle Eastern (MID) AF: 0.117 AC: 32 AN: 274

European-Non Finnish (NFE) AF: 0.128 AC: 8637 AN: 67272

Other (OTH) AF: 0.119 AC: 241 AN: 2032

Alfa AF: 0.0867 Hom.: 173

Bravo AF: 0.114

Asia WGS AF: 0.117 AC: 408 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.59
PhyloP100		0.0050
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: rs62467349; hg19: chr7-94946795;