rs3917481

Variant names:

• chr7-95321453-C-T
• rs3917481
• NM_000446.7:c.74+2949G>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.74+2949G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 152,318 control chromosomes in the GnomAD database, including 177 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 0.037 (177 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.74+2949G>A		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.74+2949G>A		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.74+2949G>A		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5674 AN: 152200 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0466

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0315

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

GnomAD4 genome AF: 0.0374 AC: 5691 AN: 152318 Hom.: 177 Cov.: 32 AF XY: 0.0382 AC XY: 2845 AN XY: 74480

African (AFR) AF: 0.0812 AC: 3375 AN: 41550

American (AMR) AF: 0.0285 AC: 436 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.0470 AC: 244 AN: 5186

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4828

European-Finnish (FIN) AF: 0.0349 AC: 371 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 833 AN: 68030

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0200 Hom.: 82

Bravo AF: 0.0392

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.31
DANN	Benign	0.63
PhyloP100		-1.3
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: rs3917481; hg19: chr7-94950765;