7-95319529-C-T

Variant names:

• chr7-95319529-C-T
• rs3917490
• NM_000446.7:c.75-1136G>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.75-1136G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,798 control chromosomes in the GnomAD database, including 22,008 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 0.53 (22008 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.75-1136G>A		intron	N/A	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.75-1136G>A		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.75-1136G>A		intron	N/A	ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80345 AN: 151680 Hom.: 21967 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.419

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.527

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

GnomAD4 genome AF: 0.530 AC: 80432 AN: 151798 Hom.: 22008 Cov.: 31 AF XY: 0.537 AC XY: 39812 AN XY: 74166

African (AFR) AF: 0.519 AC: 21446 AN: 41356

American (AMR) AF: 0.645 AC: 9835 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1507 AN: 3470

East Asian (EAS) AF: 0.961 AC: 4965 AN: 5166

South Asian (SAS) AF: 0.558 AC: 2683 AN: 4810

European-Finnish (FIN) AF: 0.494 AC: 5206 AN: 10532

Middle Eastern (MID) AF: 0.410 AC: 118 AN: 288

European-Non Finnish (NFE) AF: 0.487 AC: 33056 AN: 67906

Other (OTH) AF: 0.531 AC: 1120 AN: 2108

Alfa AF: 0.505 Hom.: 28097

Bravo AF: 0.545

Asia WGS AF: 0.746 AC: 2592 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.59
PhyloP100		-0.50
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: rs3917490; hg19: chr7-94948841;