rs854563

Variant names:

• chr7-95318697-G-A
• rs854563
• NM_000446.7:c.75-304C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000446.7(PON1):​c.75-304C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 310,866 control chromosomes in the GnomAD database, including 15,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6852 hom., cov: 32)
  • Exomes 𝑓: 0.31 (8237 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-95318697-G-A is Benign according to our data. Variant chr7-95318697-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.75-304C>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.75-304C>T		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.75-304C>T		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.75-304C>T		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42593 AN: 151972 Hom.: 6851 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.307 AC: 48779 AN: 158776 Hom.: 8237 AF XY: 0.299 AC XY: 25247 AN XY: 84436

African (AFR) AF: 0.145 AC: 757 AN: 5236

American (AMR) AF: 0.233 AC: 1743 AN: 7472

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1740 AN: 4410

East Asian (EAS) AF: 0.0477 AC: 454 AN: 9522

South Asian (SAS) AF: 0.210 AC: 4401 AN: 20928

European-Finnish (FIN) AF: 0.352 AC: 2491 AN: 7078

Middle Eastern (MID) AF: 0.338 AC: 223 AN: 660

European-Non Finnish (NFE) AF: 0.361 AC: 34159 AN: 94702

Other (OTH) AF: 0.321 AC: 2811 AN: 8768

GnomAD4 genome AF: 0.280 AC: 42592 AN: 152090 Hom.: 6852 Cov.: 32 AF XY: 0.277 AC XY: 20553 AN XY: 74326

African (AFR) AF: 0.151 AC: 6278 AN: 41486

American (AMR) AF: 0.270 AC: 4123 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1378 AN: 3472

East Asian (EAS) AF: 0.0354 AC: 183 AN: 5176

South Asian (SAS) AF: 0.201 AC: 972 AN: 4824

European-Finnish (FIN) AF: 0.349 AC: 3690 AN: 10564

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24868 AN: 67974

Other (OTH) AF: 0.313 AC: 661 AN: 2112

Alfa AF: 0.338 Hom.: 10748

Bravo AF: 0.269

Asia WGS AF: 0.119 AC: 416 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.11
DANN	Benign	0.33
PhyloP100		-1.8
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: rs854563; hg19: chr7-94948009;