7-95316141-C-T

Variant names:

• chr7-95316141-C-T
• rs3917503
• NM_000446.7:c.201+593G>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.201+593G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,940 control chromosomes in the GnomAD database, including 12,513 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 0.40 (12513 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.862
• Publications: 3 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.201+593G>A		intron_variant	Intron 3 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.201+593G>A		intron_variant	Intron 3 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.201+593G>A		intron_variant	Intron 3 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.321+593G>A		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60334 AN: 151822 Hom.: 12478 Cov.: 32

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.398 AC: 60417 AN: 151940 Hom.: 12513 Cov.: 32 AF XY: 0.400 AC XY: 29696 AN XY: 74294

African (AFR) AF: 0.480 AC: 19872 AN: 41406

American (AMR) AF: 0.433 AC: 6610 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1216 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3327 AN: 5150

South Asian (SAS) AF: 0.397 AC: 1908 AN: 4806

European-Finnish (FIN) AF: 0.333 AC: 3522 AN: 10574

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22698 AN: 67950

Other (OTH) AF: 0.402 AC: 848 AN: 2112

Alfa AF: 0.361 Hom.: 37363

Bravo AF: 0.414

Asia WGS AF: 0.542 AC: 1883 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.33
PhyloP100		-0.86
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: rs3917503; hg19: chr7-94945453;