rs13226149

Variant names:

• chr7-95396288-G-A
• rs13226149
• NM_000940.3:c.63C>T

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.63C>T​(p.Phe21Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,292 control chromosomes in the GnomAD database, including 65,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7172 hom., cov: 30)
  • Exomes 𝑓: 0.28 (58097 hom.)
• Consequence: PON3 NM_000940.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77
• Publications: 36 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

ENSG00000233942 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-95396288-G-A is Benign according to our data. Variant chr7-95396288-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 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.63C>T	p.Phe21Phe	synonymous	Exon 1 of 9	NP_000931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.63C>T	p.Phe21Phe	synonymous	Exon 1 of 9	ENSP00000265627.5
	PON3	ENST00000451904.5	TSL:3	c.63C>T	p.Phe21Phe	synonymous	Exon 1 of 9	ENSP00000403850.1
	PON3	ENST00000427422.5	TSL:3	c.63C>T	p.Phe21Phe	synonymous	Exon 1 of 7	ENSP00000413276.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45165 AN: 151612 Hom.: 7158 Cov.: 30

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.287 AC: 71408 AN: 249158 AF XY: 0.293

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.277 AC: 404529 AN: 1461562 Hom.: 58097 Cov.: 35 AF XY: 0.280 AC XY: 203898 AN XY: 727114

African (AFR) AF: 0.359 AC: 12011 AN: 33476

American (AMR) AF: 0.222 AC: 9932 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4881 AN: 26128

East Asian (EAS) AF: 0.195 AC: 7739 AN: 39700

South Asian (SAS) AF: 0.388 AC: 33494 AN: 86250

European-Finnish (FIN) AF: 0.440 AC: 23521 AN: 53416

Middle Eastern (MID) AF: 0.253 AC: 1460 AN: 5768

European-Non Finnish (NFE) AF: 0.265 AC: 294875 AN: 1111718

Other (OTH) AF: 0.275 AC: 16616 AN: 60386

GnomAD4 genome AF: 0.298 AC: 45203 AN: 151730 Hom.: 7172 Cov.: 30 AF XY: 0.305 AC XY: 22651 AN XY: 74152

African (AFR) AF: 0.341 AC: 14115 AN: 41394

American (AMR) AF: 0.237 AC: 3619 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3468

East Asian (EAS) AF: 0.179 AC: 913 AN: 5104

South Asian (SAS) AF: 0.381 AC: 1827 AN: 4794

European-Finnish (FIN) AF: 0.465 AC: 4910 AN: 10554

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18087 AN: 67860

Other (OTH) AF: 0.264 AC: 555 AN: 2102

Alfa AF: 0.266 Hom.: 17466

Bravo AF: 0.278

Asia WGS AF: 0.311 AC: 1080 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	0.21
DANN	Benign	0.86
PhyloP100		-2.8
PromoterAI		-0.010	Neutral
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: rs13226149; hg19: chr7-95025600; COSMIC: COSV55698518; COSMIC: COSV55698518;