7-95319472-A-G

Variant names:

• chr7-95319472-A-G
• rs854567
• NM_000446.7:c.75-1079T>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.75-1079T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 152,040 control chromosomes in the GnomAD database, including 47,167 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 0.78 (47167 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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.75-1079T>C		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.75-1079T>C		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.75-1079T>C		intron	N/A	ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119042 AN: 151922 Hom.: 47122 Cov.: 31

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.805

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

GnomAD4 genome AF: 0.784 AC: 119141 AN: 152040 Hom.: 47167 Cov.: 31 AF XY: 0.785 AC XY: 58345 AN XY: 74310

African (AFR) AF: 0.686 AC: 28424 AN: 41428

American (AMR) AF: 0.873 AC: 13333 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2773 AN: 3468

East Asian (EAS) AF: 0.996 AC: 5152 AN: 5174

South Asian (SAS) AF: 0.715 AC: 3443 AN: 4816

European-Finnish (FIN) AF: 0.772 AC: 8158 AN: 10572

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55183 AN: 67994

Other (OTH) AF: 0.807 AC: 1703 AN: 2110

Alfa AF: 0.802 Hom.: 79594

Bravo AF: 0.792

Asia WGS AF: 0.852 AC: 2963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.7
DANN	Benign	0.40
PhyloP100		-0.17
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: rs854567; hg19: chr7-94948784;