dbSNP rs3917564: PON1:c.781-67T>C (chr7-95302400-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000446.7(PON1):c.781-67T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,457,726 control chromosomes in the GnomAD database, including 879 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 0.047 ( 453 hom., cov: 32)

Exomes 𝑓: 0.010 ( 426 hom. )

Consequence

PON1
NM_000446.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.294

Publications

4 publications found

Variant links:

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

PON1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PON1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7 link	c.781-67T>C		intron_variant	Intron 7 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PON1	ENST00000222381.8 link	c.781-67T>C	intron_variant	Intron 7 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000462594.1 link	n.4T>C	non_coding_transcript_exon_variant	Exon 1 of 2	2
PON1	ENST00000433729.1 link	n.*506-67T>C	intron_variant	Intron 7 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes

AF:

0.0467

AC:

7099

AN:

152104

Hom.:

447

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00723

Gnomad OTH

AF:

0.0320

GnomAD4 exome

AF:

0.0101

AC:

13147

AN:

1305504

Hom.:

426

Cov.:

AF XY:

0.00952

AC XY:

6247

AN XY:

656334

show subpopulations

African (AFR)

AF:

0.154

AC:

4601

AN:

29872

American (AMR)

AF:

0.0124

AC:

532

AN:

43054

Ashkenazi Jewish (ASJ)

AF:

0.000120

AC:

AN:

25010

East Asian (EAS)

AF:

0.00

AC:

AN:

38046

South Asian (SAS)

AF:

0.00154

AC:

125

AN:

81420

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

41862

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

4540

European-Non Finnish (NFE)

AF:

0.00701

AC:

6916

AN:

986458

Other (OTH)

AF:

0.0152

AC:

841

AN:

55242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

581

1162

1743

2324

2905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.0468

AC:

7131

AN:

152222

Hom.:

453

Cov.:

AF XY:

0.0449

AC XY:

3342

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.150

AC:

6228

AN:

41498

American (AMR)

AF:

0.0205

AC:

313

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00723

AC:

492

AN:

68028

Other (OTH)

AF:

0.0317

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

308

616

925

1233

1541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0208

Hom.:

201

Bravo

AF:

0.0525

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.9

(source)

DANN

Benign

0.72

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over