dbSNP rs3917548: PON1:c.699-227T>C (chr7-95306593-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000446.7(PON1):c.699-227T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 152,212 control chromosomes in the GnomAD database, including 983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.097 ( 983 hom., cov: 32)

Consequence

PON1
NM_000446.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.454

Publications

8 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 7-95306593-A-G is Benign according to our data. Variant chr7-95306593-A-G is described in ClinVar as Benign. ClinVar VariationId is 1260730.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7 link	c.699-227T>C		intron_variant	Intron 6 of 8	ENST00000222381.8	NP_000437.3	P27169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8 link	c.699-227T>C		intron_variant	Intron 6 of 8	1	NM_000446.7	ENSP00000222381.3		P27169
PON1	ENST00000433729.1 link	n.*424-227T>C		intron_variant	Intron 6 of 8	3		ENSP00000407359.1		F8WF42

Frequencies

GnomAD3 genomes

AF:

0.0967

AC:

14703

AN:

152094

Hom.:

977

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.0718

Gnomad FIN

AF:

0.0687

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0520

Gnomad OTH

AF:

0.0860

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

GnomAD4 genome

AF:

0.0968

AC:

14733

AN:

152212

Hom.:

983

Cov.:

AF XY:

0.0974

AC XY:

7247

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.172

AC:

7136

AN:

41518

American (AMR)

AF:

0.126

AC:

1920

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0651

AC:

226

AN:

3470

East Asian (EAS)

AF:

0.119

AC:

616

AN:

5182

South Asian (SAS)

AF:

0.0709

AC:

342

AN:

4826

European-Finnish (FIN)

AF:

0.0687

AC:

729

AN:

10616

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0520

AC:

3535

AN:

68002

Other (OTH)

AF:

0.0851

AC:

180

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

641

1282

1923

2564

3205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.0703

Hom.:

953

Bravo

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.7

(source)

DANN

Benign

0.61

PhyloP100

0.45

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over