7-95320743-T-G

Variant names:

• chr7-95320743-T-G
• rs854569
• NM_000446.7:c.75-2350A>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.75-2350A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,058 control chromosomes in the GnomAD database, including 33,513 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 0.63 (33513 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.815
• Publications: 15 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-2350A>C		intron_variant	Intron 1 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.75-2350A>C		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.75-2350A>C		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96124 AN: 151940 Hom.: 33499 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.720

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.632 AC: 96163 AN: 152058 Hom.: 33513 Cov.: 32 AF XY: 0.636 AC XY: 47233 AN XY: 74318

African (AFR) AF: 0.316 AC: 13102 AN: 41456

American (AMR) AF: 0.682 AC: 10412 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2645 AN: 3468

East Asian (EAS) AF: 0.713 AC: 3676 AN: 5154

South Asian (SAS) AF: 0.603 AC: 2906 AN: 4820

European-Finnish (FIN) AF: 0.774 AC: 8184 AN: 10576

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.777 AC: 52842 AN: 67996

Other (OTH) AF: 0.683 AC: 1442 AN: 2112

Alfa AF: 0.732 Hom.: 71135

Bravo AF: 0.614

Asia WGS AF: 0.659 AC: 2296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.81
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: rs854569; hg19: chr7-94950055;