dbSNP rs147006695: PON3:p.Arg32* (chr7-95394695-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000940.3(PON3):c.94C>T(p.Arg32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 0 hom. )

Consequence

PON3
NM_000940.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.39

Publications

15 publications found

Variant links:

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

PON3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000940.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 7-95394695-G-A is Benign according to our data. Variant chr7-95394695-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488870.

BS2

High AC in GnomAd4 at 291 AD gene.

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.94C>T	p.Arg32*	stop_gained	Exon 2 of 9	NP_000931.1	Q15166

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PON3	ENST00000265627.10	TSL:1 MANE Select	c.94C>T	p.Arg32*	stop_gained	Exon 2 of 9	ENSP00000265627.5	Q15166
PON3	ENST00000902762.1		c.94C>T	p.Arg32*	stop_gained	Exon 2 of 10	ENSP00000572821.1
PON3	ENST00000902763.1		c.94C>T	p.Arg32*	stop_gained	Exon 2 of 10	ENSP00000572822.1

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

291

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00151

AC:

380

AN:

251486

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00215

AC:

3139

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1518

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00193

AC:

103

AN:

53412

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00259

AC:

2877

AN:

1111920

Other (OTH)

AF:

0.00166

AC:

100

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00191

AC:

291

AN:

152248

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41544

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00318

AC:

216

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00175

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00243

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Amyotrophic lateral sclerosis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

-0.0040

FATHMM_MKL

Benign

0.088

PhyloP100

1.4

Mutation Taster

=14/186

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.34

Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over