rs3917539

Variant names:

• chr7-95308384-T-TAA
• rs3917539
• NM_000446.7:c.498-174_498-173insTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000446.7(PON1):​c.498-174_498-173insTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.42 (15418 hom., cov: 0)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.975
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-95308384-T-TAA is Benign according to our data. Variant chr7-95308384-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 1288732.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.498-174_498-173insTT		intron_variant	Intron 5 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.498-174_498-173insTT		intron_variant	Intron 5 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*223-174_*223-173insTT		intron_variant	Intron 5 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63020 AN: 151564 Hom.: 15373 Cov.: 0

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.395

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

GnomAD4 genome AF: 0.416 AC: 63126 AN: 151678 Hom.: 15418 Cov.: 0 AF XY: 0.416 AC XY: 30826 AN XY: 74096

African (AFR) AF: 0.669 AC: 27626 AN: 41280

American (AMR) AF: 0.415 AC: 6319 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1104 AN: 3468

East Asian (EAS) AF: 0.625 AC: 3212 AN: 5138

South Asian (SAS) AF: 0.338 AC: 1630 AN: 4816

European-Finnish (FIN) AF: 0.288 AC: 3021 AN: 10500

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.279 AC: 18972 AN: 67920

Other (OTH) AF: 0.400 AC: 845 AN: 2110

Alfa AF: 0.346 Hom.: 1309

Bravo AF: 0.441

Asia WGS AF: 0.519 AC: 1802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 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
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3917539; hg19: chr7-94937696;