7-95362932-T-C

Variant names:

• chr7-95362932-T-C
• rs10953143
• NM_000940.3:c.696-91A>G

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.696-91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 839,564 control chromosomes in the GnomAD database, including 102,852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15799 hom., cov: 32)
  • Exomes 𝑓: 0.49 (87053 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.263
• 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=-0.86).
• BP6: Variant 7-95362932-T-C is Benign according to our data. Variant chr7-95362932-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.719 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.696-91A>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.696-91A>G		intron	N/A	ENSP00000265627.5	Q15166
	PON3	ENST00000902762.1		c.879-91A>G		intron	N/A	ENSP00000572821.1
	PON3	ENST00000902763.1		c.849-91A>G		intron	N/A	ENSP00000572822.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66919 AN: 151830 Hom.: 15792 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.490 AC: 337194 AN: 687616 Hom.: 87053 AF XY: 0.495 AC XY: 181714 AN XY: 367412

African (AFR) AF: 0.293 AC: 5436 AN: 18548

American (AMR) AF: 0.621 AC: 23861 AN: 38436

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 8155 AN: 20920

East Asian (EAS) AF: 0.770 AC: 26776 AN: 34788

South Asian (SAS) AF: 0.606 AC: 40977 AN: 67576

European-Finnish (FIN) AF: 0.566 AC: 24233 AN: 42832

Middle Eastern (MID) AF: 0.413 AC: 1381 AN: 3340

European-Non Finnish (NFE) AF: 0.446 AC: 190109 AN: 426370

Other (OTH) AF: 0.467 AC: 16266 AN: 34806

GnomAD4 genome AF: 0.441 AC: 66947 AN: 151948 Hom.: 15799 Cov.: 32 AF XY: 0.455 AC XY: 33813 AN XY: 74262

African (AFR) AF: 0.292 AC: 12109 AN: 41460

American (AMR) AF: 0.541 AC: 8247 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1403 AN: 3472

East Asian (EAS) AF: 0.738 AC: 3818 AN: 5170

South Asian (SAS) AF: 0.619 AC: 2978 AN: 4814

European-Finnish (FIN) AF: 0.591 AC: 6239 AN: 10550

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

European-Non Finnish (NFE) AF: 0.450 AC: 30557 AN: 67924

Other (OTH) AF: 0.439 AC: 926 AN: 2110

Alfa AF: 0.448 Hom.: 66695

Bravo AF: 0.430

Asia WGS AF: 0.649 AC: 2256 AN: 3478

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	-0.86
CADD	Benign	4.0
DANN	Benign	0.53
PhyloP100		0.26
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: rs10953143; hg19: chr7-94992244; COSMIC: COSV55698580; COSMIC: COSV55698580;