chr7-95313453-A-C

Variant names:

• chr7-95313453-A-C
• rs2299257
• NM_000446.7:c.370+1869T>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.370+1869T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,054 control chromosomes in the GnomAD database, including 16,193 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 0.45 (16193 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748
• Publications: 14 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.370+1869T>G		intron_variant	Intron 4 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.370+1869T>G		intron_variant	Intron 4 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*95+1869T>G		intron_variant	Intron 4 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.490+1869T>G		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68360 AN: 151934 Hom.: 16154 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.450 AC: 68456 AN: 152054 Hom.: 16193 Cov.: 32 AF XY: 0.450 AC XY: 33449 AN XY: 74304

African (AFR) AF: 0.583 AC: 24169 AN: 41472

American (AMR) AF: 0.459 AC: 7016 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1250 AN: 3466

East Asian (EAS) AF: 0.646 AC: 3338 AN: 5168

South Asian (SAS) AF: 0.398 AC: 1914 AN: 4810

European-Finnish (FIN) AF: 0.370 AC: 3915 AN: 10568

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25466 AN: 67970

Other (OTH) AF: 0.442 AC: 931 AN: 2106

Alfa AF: 0.404 Hom.: 17050

Bravo AF: 0.468

Asia WGS AF: 0.549 AC: 1908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		-0.75
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: rs2299257; hg19: chr7-94942765;