7-95319437-A-G

Variant names:

• chr7-95319437-A-G
• rs854566
• NM_000446.7:c.75-1044T>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.75-1044T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 152,082 control chromosomes in the GnomAD database, including 47,180 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 0.78 (47180 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.915
• Publications: 10 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 = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-1044T>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.75-1044T>C		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.75-1044T>C		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119072 AN: 151964 Hom.: 47135 Cov.: 31

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.805

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

GnomAD4 genome AF: 0.784 AC: 119171 AN: 152082 Hom.: 47180 Cov.: 31 AF XY: 0.785 AC XY: 58361 AN XY: 74336

African (AFR) AF: 0.686 AC: 28428 AN: 41438

American (AMR) AF: 0.873 AC: 13349 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2777 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5152 AN: 5174

South Asian (SAS) AF: 0.715 AC: 3448 AN: 4822

European-Finnish (FIN) AF: 0.772 AC: 8155 AN: 10570

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55189 AN: 67998

Other (OTH) AF: 0.807 AC: 1700 AN: 2106

Alfa AF: 0.794 Hom.: 15213

Bravo AF: 0.792

Asia WGS AF: 0.852 AC: 2963 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	1.0
DANN	Benign	0.55
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs854566; hg19: chr7-94948749;