chr7-95303877-T-C

Variant names:

• chr7-95303877-T-C
• rs3917556
• NM_000446.7:c.781-1544A>G

Variant summary

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

The NM_000446.7(PON1):​c.781-1544A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 152,244 control chromosomes in the GnomAD database, including 827 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 0.091 (827 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.783
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 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.781-1544A>G		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.781-1544A>G		intron	N/A	ENSP00000222381.3
	PON1	ENST00000893040.1		c.772-1544A>G		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.781-1592A>G		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13763 AN: 152126 Hom.: 824 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0812

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

GnomAD4 genome AF: 0.0905 AC: 13783 AN: 152244 Hom.: 827 Cov.: 32 AF XY: 0.0907 AC XY: 6755 AN XY: 74436

African (AFR) AF: 0.150 AC: 6207 AN: 41506

American (AMR) AF: 0.124 AC: 1902 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.119 AC: 620 AN: 5190

South Asian (SAS) AF: 0.0708 AC: 342 AN: 4828

European-Finnish (FIN) AF: 0.0691 AC: 733 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0520 AC: 3535 AN: 68018

Other (OTH) AF: 0.0803 AC: 170 AN: 2116

Alfa AF: 0.0685 Hom.: 1327

Bravo AF: 0.0995

Asia WGS AF: 0.0900 AC: 314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.47
PhyloP100		-0.78
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: rs3917556; hg19: chr7-94933189;