7-95316560-G-A

Variant names:

• chr7-95316560-G-A
• rs854559
• NM_000446.7:c.201+174C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000446.7(PON1):​c.201+174C>T 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 152,030 control chromosomes in the GnomAD database, including 7,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7017 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.809
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-95316560-G-A is Benign according to our data. Variant chr7-95316560-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230450.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.201+174C>T		intron	N/A	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.201+174C>T		intron	N/A	ENSP00000222381.3
	PON1	ENST00000893040.1		c.201+174C>T		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.201+174C>T		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43641 AN: 151912 Hom.: 7015 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0362

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.287 AC: 43652 AN: 152030 Hom.: 7017 Cov.: 33 AF XY: 0.284 AC XY: 21082 AN XY: 74296

African (AFR) AF: 0.175 AC: 7261 AN: 41472

American (AMR) AF: 0.273 AC: 4171 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1376 AN: 3468

East Asian (EAS) AF: 0.0365 AC: 189 AN: 5180

South Asian (SAS) AF: 0.201 AC: 970 AN: 4818

European-Finnish (FIN) AF: 0.351 AC: 3704 AN: 10546

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24875 AN: 67952

Other (OTH) AF: 0.315 AC: 665 AN: 2110

Alfa AF: 0.335 Hom.: 11355

Bravo AF: 0.277

Asia WGS AF: 0.118 AC: 413 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.20
DANN	Benign	0.62
PhyloP100		-0.81
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: rs854559; hg19: chr7-94945872;