7-95363596-G-A

Variant names:

• chr7-95363596-G-A
• rs2074353
• NM_000940.3:c.695+267C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000940.3(PON3):​c.695+267C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 487,068 control chromosomes in the GnomAD database, including 58,726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15798 hom., cov: 32)
  • Exomes 𝑓: 0.49 (42928 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.648
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-95363596-G-A is Benign according to our data. Variant chr7-95363596-G-A is described in ClinVar as Benign. ClinVar VariationId is 1239780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3	c.695+267C>T		intron_variant	Intron 6 of 8	ENST00000265627.10	NP_000931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10	c.695+267C>T		intron_variant	Intron 6 of 8	1	NM_000940.3	ENSP00000265627.5

Frequencies

GnomAD3 genomes AF: 0.442 AC: 66920 AN: 151544 Hom.: 15791 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.494 AC: 165578 AN: 335410 Hom.: 42928 Cov.: 2 AF XY: 0.501 AC XY: 89715 AN XY: 179100

African (AFR) AF: 0.305 AC: 3006 AN: 9856

American (AMR) AF: 0.588 AC: 8881 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 3884 AN: 10022

East Asian (EAS) AF: 0.766 AC: 15652 AN: 20438

South Asian (SAS) AF: 0.605 AC: 25734 AN: 42532

European-Finnish (FIN) AF: 0.555 AC: 9822 AN: 17690

Middle Eastern (MID) AF: 0.416 AC: 602 AN: 1446

European-Non Finnish (NFE) AF: 0.447 AC: 89040 AN: 199198

Other (OTH) AF: 0.468 AC: 8957 AN: 19124

GnomAD4 genome AF: 0.441 AC: 66948 AN: 151658 Hom.: 15798 Cov.: 32 AF XY: 0.456 AC XY: 33819 AN XY: 74138

African (AFR) AF: 0.294 AC: 12115 AN: 41154

American (AMR) AF: 0.541 AC: 8257 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1401 AN: 3470

East Asian (EAS) AF: 0.737 AC: 3802 AN: 5158

South Asian (SAS) AF: 0.619 AC: 2984 AN: 4820

European-Finnish (FIN) AF: 0.591 AC: 6248 AN: 10564

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30542 AN: 67928

Other (OTH) AF: 0.440 AC: 928 AN: 2108

Alfa AF: 0.445 Hom.: 19281

Bravo AF: 0.430

Asia WGS AF: 0.649 AC: 2255 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.3
DANN	Benign	0.68
PhyloP100		-0.65
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: rs2074353; hg19: chr7-94992908;