7-95302632-GAA-GAAAA

Variant names:

• chr7-95302632-G-GAA
• rs142523546
• NM_000446.7:c.781-301_781-300dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000446.7(PON1):​c.781-301_781-300dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 146,874 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000089 (0 hom., cov: 28)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.781-301_781-300dupTT		intron_variant	Intron 7 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.781-300_781-299insTT		intron_variant	Intron 7 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*506-300_*506-299insTT		intron_variant	Intron 7 of 8	3		ENSP00000407359.1
PON1	ENST00000462594.1	n.-230_-229insTT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000886 AC: 13 AN: 146772 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.0000885 AC: 13 AN: 146874 Hom.: 0 Cov.: 28 AF XY: 0.0000561 AC XY: 4 AN XY: 71364

African (AFR) AF: 0.000299 AC: 12 AN: 40196

American (AMR) AF: 0.00 AC: 0 AN: 14814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66264

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 48

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061

Splicing

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

Other links and lift over

dbSNP: rs142523546; hg19: chr7-94931944;