7-95320017-A-G

Variant names:

• chr7-95320017-A-G
• rs2049649
• NM_000446.7:c.75-1624T>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.75-1624T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,096 control chromosomes in the GnomAD database, including 12,011 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 0.38 (12011 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.899
• Publications: 9 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 (EAS) allele frequency at 95% confidence interval = 0.858 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.75-1624T>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.75-1624T>C		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.75-1624T>C		intron	N/A	ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57526 AN: 151978 Hom.: 11987 Cov.: 33

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.379 AC: 57589 AN: 152096 Hom.: 12011 Cov.: 33 AF XY: 0.383 AC XY: 28457 AN XY: 74348

African (AFR) AF: 0.411 AC: 17060 AN: 41476

American (AMR) AF: 0.481 AC: 7356 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3470

East Asian (EAS) AF: 0.879 AC: 4554 AN: 5182

South Asian (SAS) AF: 0.428 AC: 2062 AN: 4820

European-Finnish (FIN) AF: 0.255 AC: 2694 AN: 10562

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.320 AC: 21785 AN: 67980

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.339 Hom.: 2205

Bravo AF: 0.402

Asia WGS AF: 0.617 AC: 2141 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	0.33
DANN	Benign	0.41
PhyloP100		-0.90
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: rs2049649; hg19: chr7-94949329;