rs2057682

Variant names:

• chr7-95361452-G-C
• rs2057682
• NM_000940.3:c.906+910C>G

Variant summary

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

The NM_000940.3(PON3):​c.906+910C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 151,972 control chromosomes in the GnomAD database, including 2,073 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 0.15 (2073 hom., cov: 32)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.798
• Publications: 3 publications found

Genes affected

PON3 (HGNC:9206): (paraoxonase 3) This gene is a member of the paraoxonase family and lies in a cluster on chromosome 7 with the other two family members. The encoded protein is secreted into the bloodstream and associates with high-density lipoprotein (HDL). The protein also rapidly hydrolyzes lactones and can inhibit the oxidation of low-density lipoprotein (LDL), a function that is believed to slow the initiation and progression of atherosclerosis. Alternatively spliced variants which encode different protein isoforms have been described; however, only one has been fully characterized. [provided by RefSeq, Jul 2008]

PON3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000940.3. 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
	PON3	NM_000940.3	MANE Select	c.906+910C>G		intron	N/A	NP_000931.1	Q15166

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.906+910C>G		intron	N/A	ENSP00000265627.5	Q15166
	PON3	ENST00000902762.1		c.1089+910C>G		intron	N/A	ENSP00000572821.1
	PON3	ENST00000902763.1		c.1059+910C>G		intron	N/A	ENSP00000572822.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22741 AN: 151854 Hom.: 2071 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.0813

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.150 AC: 22752 AN: 151972 Hom.: 2073 Cov.: 32 AF XY: 0.145 AC XY: 10761 AN XY: 74330

African (AFR) AF: 0.251 AC: 10395 AN: 41428

American (AMR) AF: 0.101 AC: 1547 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1092 AN: 5164

South Asian (SAS) AF: 0.0779 AC: 375 AN: 4816

European-Finnish (FIN) AF: 0.0813 AC: 860 AN: 10576

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7725 AN: 67932

Other (OTH) AF: 0.129 AC: 272 AN: 2110

Alfa AF: 0.138 Hom.: 220

Bravo AF: 0.157

Asia WGS AF: 0.156 AC: 540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		0.80
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2057682;

hg19: chr7-94990764;