7-95317259-G-T

Variant names:

• chr7-95317259-G-T
• rs705378
• NM_000446.7:c.146-470C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.146-470C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 151,986 control chromosomes in the GnomAD database, including 7,012 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 0.29 (7012 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.146-470C>A		intron	N/A	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.146-470C>A		intron	N/A	ENSP00000222381.3
	PON1	ENST00000893040.1		c.146-470C>A		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.146-470C>A		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43615 AN: 151866 Hom.: 7010 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.287 AC: 43626 AN: 151986 Hom.: 7012 Cov.: 32 AF XY: 0.284 AC XY: 21057 AN XY: 74274

African (AFR) AF: 0.175 AC: 7259 AN: 41482

American (AMR) AF: 0.273 AC: 4160 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1374 AN: 3468

East Asian (EAS) AF: 0.0359 AC: 186 AN: 5176

South Asian (SAS) AF: 0.201 AC: 970 AN: 4820

European-Finnish (FIN) AF: 0.351 AC: 3693 AN: 10528

Middle Eastern (MID) AF: 0.434 AC: 126 AN: 290

European-Non Finnish (NFE) AF: 0.366 AC: 24875 AN: 67934

Other (OTH) AF: 0.316 AC: 668 AN: 2116

Alfa AF: 0.308 Hom.: 1112

Bravo AF: 0.277

Asia WGS AF: 0.116 AC: 403 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.0
DANN	Benign	0.55
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs705378; hg19: chr7-94946571;