7-95392491-T-G

Variant names:

• chr7-95392491-T-G
• rs740264
• NM_000940.3:c.145+2153A>C

Variant summary

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

The NM_000940.3(PON3):​c.145+2153A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,126 control chromosomes in the GnomAD database, including 5,143 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 0.25 (5143 hom., cov: 32)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.136
• Publications: 8 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3	c.145+2153A>C		intron_variant	Intron 2 of 8	ENST00000265627.10	NP_000931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10	c.145+2153A>C		intron_variant	Intron 2 of 8	1	NM_000940.3	ENSP00000265627.5

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37747 AN: 152008 Hom.: 5135 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.248 AC: 37766 AN: 152126 Hom.: 5143 Cov.: 32 AF XY: 0.257 AC XY: 19114 AN XY: 74356

African (AFR) AF: 0.199 AC: 8274 AN: 41506

American (AMR) AF: 0.210 AC: 3206 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3472

East Asian (EAS) AF: 0.147 AC: 761 AN: 5176

South Asian (SAS) AF: 0.365 AC: 1757 AN: 4818

European-Finnish (FIN) AF: 0.436 AC: 4603 AN: 10558

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17527 AN: 67978

Other (OTH) AF: 0.232 AC: 491 AN: 2116

Alfa AF: 0.233 Hom.: 5298

Bravo AF: 0.224

Asia WGS AF: 0.266 AC: 925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.82
PhyloP100		-0.14
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: rs740264; hg19: chr7-95021803;