rs1053275

Variant names:

• chr7-95372243-C-T
• rs1053275
• NM_000940.3:c.297G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000940.3(PON3):​c.297G>A​(p.Ala99Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,612,772 control chromosomes in the GnomAD database, including 218,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22797 hom., cov: 32)
  • Exomes 𝑓: 0.51 (195610 hom.)
• Consequence: PON3 NM_000940.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0810
• Publications: 42 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-95372243-C-T is Benign according to our data. Variant chr7-95372243-C-T is described in ClinVar as Benign. ClinVar VariationId is 1289181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.762 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.297G>A	p.Ala99Ala	synonymous	Exon 4 of 9	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.297G>A	p.Ala99Ala	synonymous	Exon 4 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000902762.1		c.441G>A	p.Ala147Ala	synonymous	Exon 5 of 10	ENSP00000572821.1
	PON3	ENST00000902763.1		c.441G>A	p.Ala147Ala	synonymous	Exon 5 of 10	ENSP00000572822.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82082 AN: 151792 Hom.: 22743 Cov.: 32

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.516

GnomAD2 exomes AF: 0.571 AC: 143582 AN: 251258 AF XY: 0.569

Gnomad AFR exome AF: 0.580

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.509 AC: 744296 AN: 1460862 Hom.: 195610 Cov.: 49 AF XY: 0.513 AC XY: 372834 AN XY: 726788

African (AFR) AF: 0.585 AC: 19551 AN: 33446

American (AMR) AF: 0.698 AC: 31213 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10629 AN: 26128

East Asian (EAS) AF: 0.821 AC: 32577 AN: 39678

South Asian (SAS) AF: 0.677 AC: 58399 AN: 86236

European-Finnish (FIN) AF: 0.602 AC: 32122 AN: 53398

Middle Eastern (MID) AF: 0.442 AC: 2550 AN: 5764

European-Non Finnish (NFE) AF: 0.473 AC: 525910 AN: 1111146

Other (OTH) AF: 0.519 AC: 31345 AN: 60362

GnomAD4 genome AF: 0.541 AC: 82194 AN: 151910 Hom.: 22797 Cov.: 32 AF XY: 0.555 AC XY: 41207 AN XY: 74234

African (AFR) AF: 0.573 AC: 23718 AN: 41408

American (AMR) AF: 0.613 AC: 9363 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3470

East Asian (EAS) AF: 0.782 AC: 4034 AN: 5160

South Asian (SAS) AF: 0.690 AC: 3324 AN: 4818

European-Finnish (FIN) AF: 0.627 AC: 6610 AN: 10548

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31906 AN: 67928

Other (OTH) AF: 0.521 AC: 1098 AN: 2108

Alfa AF: 0.493 Hom.: 65636

Bravo AF: 0.541

Asia WGS AF: 0.737 AC: 2561 AN: 3476

EpiCase AF: 0.464

EpiControl AF: 0.468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.5
DANN	Benign	0.67
PhyloP100		0.081
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: rs1053275; hg19: chr7-95001555; COSMIC: COSV55699327;