7-95310928-C-G

Variant names:

• chr7-95310928-C-G
• rs3917528
• NM_000446.7:c.497+523G>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.497+523G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 151,952 control chromosomes in the GnomAD database, including 2,289 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 0.15 (2289 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.497+523G>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.497+523G>C		intron_variant	Intron 5 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*222+523G>C		intron_variant	Intron 5 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23272 AN: 151832 Hom.: 2284 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.153 AC: 23296 AN: 151952 Hom.: 2289 Cov.: 32 AF XY: 0.154 AC XY: 11420 AN XY: 74270

African (AFR) AF: 0.248 AC: 10250 AN: 41388

American (AMR) AF: 0.147 AC: 2238 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3470

East Asian (EAS) AF: 0.430 AC: 2203 AN: 5126

South Asian (SAS) AF: 0.171 AC: 822 AN: 4812

European-Finnish (FIN) AF: 0.0468 AC: 495 AN: 10588

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6308 AN: 67982

Other (OTH) AF: 0.166 AC: 351 AN: 2114

Alfa AF: 0.0465 Hom.: 40

Bravo AF: 0.167

Asia WGS AF: 0.285 AC: 988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.28
PhyloP100		0.036
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: rs3917528; hg19: chr7-94940240;