7-95308581-G-A

Variant names:

• chr7-95308581-G-A
• rs3917538
• NM_000446.7:c.498-370C>T

Variant summary

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

The NM_000446.7(PON1):​c.498-370C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 151,808 control chromosomes in the GnomAD database, including 8,914 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 0.32 (8914 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174
• Publications: 13 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=-0.57).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.498-370C>T		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.498-370C>T		intron_variant	Intron 5 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*223-370C>T		intron_variant	Intron 5 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48639 AN: 151690 Hom.: 8884 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.310

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

GnomAD4 genome AF: 0.321 AC: 48718 AN: 151808 Hom.: 8914 Cov.: 31 AF XY: 0.320 AC XY: 23770 AN XY: 74176

African (AFR) AF: 0.501 AC: 20729 AN: 41370

American (AMR) AF: 0.289 AC: 4409 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3470

East Asian (EAS) AF: 0.507 AC: 2605 AN: 5140

South Asian (SAS) AF: 0.267 AC: 1282 AN: 4800

European-Finnish (FIN) AF: 0.222 AC: 2336 AN: 10514

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15459 AN: 67954

Other (OTH) AF: 0.317 AC: 668 AN: 2108

Alfa AF: 0.253 Hom.: 5741

Bravo AF: 0.335

Asia WGS AF: 0.417 AC: 1447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		0.17
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: rs3917538; hg19: chr7-94937893;