rs468

Variant names:

• chr7-95368641-A-G
• rs468
• NM_000940.3:c.368-1153T>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.368-1153T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 152,158 control chromosomes in the GnomAD database, including 330 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 0.053 (330 hom., cov: 32)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	NM_000940.3	MANE Select	c.368-1153T>C		intron	N/A	NP_000931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.368-1153T>C		intron	N/A	ENSP00000265627.5
	PON3	ENST00000451904.5	TSL:3	c.368-1153T>C		intron	N/A	ENSP00000403850.1
	PON3	ENST00000427422.5	TSL:3	c.368-1153T>C		intron	N/A	ENSP00000413276.1

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8139 AN: 152040 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0446

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

GnomAD4 genome AF: 0.0535 AC: 8138 AN: 152158 Hom.: 330 Cov.: 32 AF XY: 0.0536 AC XY: 3987 AN XY: 74378

African (AFR) AF: 0.0302 AC: 1253 AN: 41548

American (AMR) AF: 0.0291 AC: 445 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.183 AC: 944 AN: 5158

South Asian (SAS) AF: 0.0562 AC: 271 AN: 4826

European-Finnish (FIN) AF: 0.0578 AC: 611 AN: 10580

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0632 AC: 4294 AN: 67990

Other (OTH) AF: 0.0446 AC: 94 AN: 2106

Alfa AF: 0.0580 Hom.: 461

Bravo AF: 0.0513

Asia WGS AF: 0.119 AC: 414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.49
PhyloP100		1.1
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: rs468; hg19: chr7-94997953;