NM_000446.7:c.74+1748T>C

Variant names:

• chr7-95322654-A-G
• rs3917477
• NM_000446.7:c.74+1748T>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.74+1748T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 152,248 control chromosomes in the GnomAD database, including 622 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 0.074 (622 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.56
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.74+1748T>C		intron	N/A	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.74+1748T>C		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.74+1748T>C		intron	N/A	ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11179 AN: 152130 Hom.: 617 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0598

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

GnomAD4 genome AF: 0.0736 AC: 11201 AN: 152248 Hom.: 622 Cov.: 31 AF XY: 0.0739 AC XY: 5503 AN XY: 74440

African (AFR) AF: 0.141 AC: 5857 AN: 41538

American (AMR) AF: 0.108 AC: 1652 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3468

East Asian (EAS) AF: 0.115 AC: 593 AN: 5166

South Asian (SAS) AF: 0.0415 AC: 200 AN: 4822

European-Finnish (FIN) AF: 0.0353 AC: 375 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0332 AC: 2259 AN: 68022

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0476 Hom.: 1026

Bravo AF: 0.0840

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.79
PhyloP100		-4.6
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: rs3917477; hg19: chr7-94951966;