NM_000446.7:c.146-154C>A

Variant names:

• chr7-95316943-G-T
• rs3917498
• NM_000446.7:c.146-154C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000446.7(PON1):​c.146-154C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 151,974 control chromosomes in the GnomAD database, including 12,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.40 (12467 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.997

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-95316943-G-T is Benign according to our data. Variant chr7-95316943-G-T is described in ClinVar as [Benign]. Clinvar id is 1225160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.146-154C>A		intron_variant	Intron 2 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.146-154C>A		intron_variant	Intron 2 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.146-154C>A		intron_variant	Intron 2 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.266-154C>A		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60268 AN: 151856 Hom.: 12434 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.397 AC: 60349 AN: 151974 Hom.: 12467 Cov.: 33 AF XY: 0.399 AC XY: 29638 AN XY: 74266

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.432

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.402

Alfa AF: 0.357 Hom.: 6688

Bravo AF: 0.413

Asia WGS AF: 0.541 AC: 1878 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.79
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs3917498; hg19: chr7-94946255;