NM_000446.7:c.909+246A>G

Variant names:

• chr7-95301959-T-C
• rs7792044
• NM_000446.7:c.909+246A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000446.7(PON1):​c.909+246A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 148,780 control chromosomes in the GnomAD database, including 937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (937 hom., cov: 25)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.418
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 7-95301959-T-C is Benign according to our data. Variant chr7-95301959-T-C is described in ClinVar as Benign. ClinVar VariationId is 1233629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.909+246A>G		intron	N/A	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.909+246A>G		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.900+246A>G		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.861+246A>G		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15152 AN: 148724 Hom.: 934 Cov.: 25

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0901

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

GnomAD4 genome AF: 0.102 AC: 15168 AN: 148780 Hom.: 937 Cov.: 25 AF XY: 0.104 AC XY: 7560 AN XY: 72372

African (AFR) AF: 0.153 AC: 6202 AN: 40438

American (AMR) AF: 0.136 AC: 2039 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 239 AN: 3452

East Asian (EAS) AF: 0.118 AC: 592 AN: 5036

South Asian (SAS) AF: 0.0726 AC: 340 AN: 4680

European-Finnish (FIN) AF: 0.124 AC: 1186 AN: 9590

Middle Eastern (MID) AF: 0.0870 AC: 24 AN: 276

European-Non Finnish (NFE) AF: 0.0642 AC: 4325 AN: 67356

Other (OTH) AF: 0.0894 AC: 183 AN: 2046

Alfa AF: 0.0801 Hom.: 71

Bravo AF: 0.108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.7
DANN	Benign	0.18
PhyloP100		0.42
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: rs7792044; hg19: chr7-94931271;