NM_000446.7:c.909+1126T>G

Variant names:

• chr7-95301079-A-C
• rs854555
• NM_000446.7:c.909+1126T>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.909+1126T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 151,590 control chromosomes in the GnomAD database, including 23,488 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 0.54 (23488 hom., cov: 30)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 38 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.909+1126T>G		intron_variant	Intron 8 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.909+1126T>G		intron_variant	Intron 8 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*634+1126T>G		intron_variant	Intron 8 of 8	3		ENSP00000407359.1
PON1	ENST00000462594.1	n.199+1126T>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81565 AN: 151472 Hom.: 23493 Cov.: 30

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.564

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

GnomAD4 genome AF: 0.538 AC: 81572 AN: 151590 Hom.: 23488 Cov.: 30 AF XY: 0.538 AC XY: 39808 AN XY: 74024

African (AFR) AF: 0.325 AC: 13413 AN: 41306

American (AMR) AF: 0.573 AC: 8732 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2143 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2068 AN: 5148

South Asian (SAS) AF: 0.607 AC: 2912 AN: 4796

European-Finnish (FIN) AF: 0.591 AC: 6185 AN: 10458

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44146 AN: 67882

Other (OTH) AF: 0.559 AC: 1172 AN: 2098

Alfa AF: 0.611 Hom.: 125374

Bravo AF: 0.524

Asia WGS AF: 0.466 AC: 1622 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.79
PhyloP100		-0.62
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: rs854555; hg19: chr7-94930391;