rs2074351

Positions:

• chr7-95318487-G-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.75-94C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,156,122 control chromosomes in the GnomAD database, including 49,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5592 hom., cov: 32)
  • Exomes 𝑓: 0.29 (44376 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-95318487-G-A is Benign according to our data. Variant chr7-95318487-G-A is described in ClinVar as [Benign]. Clinvar id is 1288755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON1	NM_000446.7	c.75-94C>T		intron_variant		ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.75-94C>T		intron_variant		1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000470502.1	n.101C>T		non_coding_transcript_exon_variant	1/4	4
PON1	ENST00000433729.1	n.75-94C>T		intron_variant		3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39961 AN: 151976 Hom.: 5585 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.289 AC: 290159 AN: 1004028 Hom.: 44376 Cov.: 13 AF XY: 0.290 AC XY: 149711 AN XY: 517118

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.548

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.263 AC: 39990 AN: 152094 Hom.: 5592 Cov.: 32 AF XY: 0.266 AC XY: 19779 AN XY: 74352

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.525

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.286

Alfa AF: 0.280 Hom.: 6792

Bravo AF: 0.264

Asia WGS AF: 0.430 AC: 1495 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.6
DANN	Benign	0.50

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: rs2074351; hg19: chr7-94947799; COSMIC: COSV55931030;