7-95306817-A-G

Variant names:

• chr7-95306817-A-G
• rs2269829
• NM_000446.7:c.699-451T>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.699-451T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,778 control chromosomes in the GnomAD database, including 11,899 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 0.38 (11899 hom., cov: 30)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 14 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.699-451T>C		intron_variant	Intron 6 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.699-451T>C		intron_variant	Intron 6 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*424-451T>C		intron_variant	Intron 6 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56911 AN: 151660 Hom.: 11866 Cov.: 30

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.376 AC: 56996 AN: 151778 Hom.: 11899 Cov.: 30 AF XY: 0.377 AC XY: 27991 AN XY: 74168

African (AFR) AF: 0.541 AC: 22358 AN: 41364

American (AMR) AF: 0.395 AC: 6018 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1095 AN: 3466

East Asian (EAS) AF: 0.624 AC: 3208 AN: 5140

South Asian (SAS) AF: 0.337 AC: 1619 AN: 4802

European-Finnish (FIN) AF: 0.289 AC: 3040 AN: 10518

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18491 AN: 67928

Other (OTH) AF: 0.370 AC: 778 AN: 2100

Alfa AF: 0.312 Hom.: 11429

Bravo AF: 0.395

Asia WGS AF: 0.506 AC: 1758 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.40
DANN	Benign	0.61
PhyloP100		-1.2
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: rs2269829; hg19: chr7-94936129;