7-95298365-A-G

Variant names:

• chr7-95298365-A-G
• rs854551
• NM_000446.7:c.*579T>C

Variant summary

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

The NM_000446.7(PON1):​c.*579T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 160,400 control chromosomes in the GnomAD database, including 51,658 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 0.80 (48571 hom., cov: 32)
  • Exomes 𝑓: 0.86 (3087 hom.)
• Consequence: PON1 NM_000446.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.637
• Publications: 18 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.882 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.*579T>C		3_prime_UTR	Exon 9 of 9	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.*579T>C		3_prime_UTR	Exon 9 of 9	ENSP00000222381.3

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121290 AN: 152036 Hom.: 48535 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.824

GnomAD4 exome AF: 0.862 AC: 7111 AN: 8246 Hom.: 3087 Cov.: 0 AF XY: 0.860 AC XY: 3684 AN XY: 4282

African (AFR) AF: 0.818 AC: 36 AN: 44

American (AMR) AF: 0.897 AC: 1847 AN: 2060

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 63 AN: 72

East Asian (EAS) AF: 0.924 AC: 695 AN: 752

South Asian (SAS) AF: 0.894 AC: 830 AN: 928

European-Finnish (FIN) AF: 0.896 AC: 43 AN: 48

Middle Eastern (MID) AF: 0.875 AC: 7 AN: 8

European-Non Finnish (NFE) AF: 0.826 AC: 3314 AN: 4014

Other (OTH) AF: 0.863 AC: 276 AN: 320

GnomAD4 genome AF: 0.798 AC: 121381 AN: 152154 Hom.: 48571 Cov.: 32 AF XY: 0.800 AC XY: 59544 AN XY: 74392

African (AFR) AF: 0.758 AC: 31418 AN: 41474

American (AMR) AF: 0.852 AC: 13036 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2980 AN: 3472

East Asian (EAS) AF: 0.904 AC: 4683 AN: 5180

South Asian (SAS) AF: 0.871 AC: 4194 AN: 4814

European-Finnish (FIN) AF: 0.751 AC: 7943 AN: 10578

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54489 AN: 68022

Other (OTH) AF: 0.818 AC: 1730 AN: 2114

Alfa AF: 0.806 Hom.: 133573

Bravo AF: 0.804

Asia WGS AF: 0.849 AC: 2953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.9
DANN	Benign	0.44
PhyloP100		0.64
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: rs854551; hg19: chr7-94927677;