chr7-95303592-T-C

Variant names:

• chr7-95303592-T-C
• rs3917558
• NM_000446.7:c.781-1259A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.781-1259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 152,096 control chromosomes in the GnomAD database, including 4,090 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 0.17 (4090 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.15
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.781-1259A>G		intron_variant	Intron 7 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.781-1259A>G		intron_variant	Intron 7 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*506-1259A>G		intron_variant	Intron 7 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25867 AN: 151978 Hom.: 4075 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.138

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

GnomAD4 genome AF: 0.170 AC: 25916 AN: 152096 Hom.: 4090 Cov.: 32 AF XY: 0.166 AC XY: 12363 AN XY: 74352

African (AFR) AF: 0.415 AC: 17192 AN: 41398

American (AMR) AF: 0.155 AC: 2369 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3468

East Asian (EAS) AF: 0.119 AC: 616 AN: 5174

South Asian (SAS) AF: 0.0728 AC: 352 AN: 4832

European-Finnish (FIN) AF: 0.0701 AC: 744 AN: 10608

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0598 AC: 4068 AN: 68014

Other (OTH) AF: 0.137 AC: 288 AN: 2108

Alfa AF: 0.107 Hom.: 2220

Bravo AF: 0.189

Asia WGS AF: 0.107 AC: 373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.046
DANN	Benign	0.69
PhyloP100		-2.2
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: rs3917558; hg19: chr7-94932904;