rs705381

Variant names:

• chr7-95324637-T-C
• rs705381
• NM_000446.7:c.-162A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000446.7(PON1):​c.-162A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 701,980 control chromosomes in the GnomAD database, including 200,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40603 hom., cov: 34)
  • Exomes 𝑓: 0.76 (159582 hom.)
• Consequence: PON1 NM_000446.7 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.332
• Publications: 75 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-95324637-T-C is Benign according to our data. Variant chr7-95324637-T-C is described in ClinVar as Benign. ClinVar VariationId is 1268484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.-162A>G		upstream_gene_variant		ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.-162A>G		upstream_gene_variant		1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.-162A>G		upstream_gene_variant		3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110386 AN: 152048 Hom.: 40564 Cov.: 34

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.786

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.756

GnomAD4 exome AF: 0.760 AC: 417587 AN: 549816 Hom.: 159582 Cov.: 6 AF XY: 0.756 AC XY: 222248 AN XY: 293806

African (AFR) AF: 0.603 AC: 9359 AN: 15526

American (AMR) AF: 0.812 AC: 26231 AN: 32320

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 14564 AN: 18024

East Asian (EAS) AF: 0.884 AC: 28071 AN: 31748

South Asian (SAS) AF: 0.711 AC: 40948 AN: 57608

European-Finnish (FIN) AF: 0.775 AC: 27406 AN: 35382

Middle Eastern (MID) AF: 0.784 AC: 1952 AN: 2490

European-Non Finnish (NFE) AF: 0.754 AC: 246451 AN: 326852

Other (OTH) AF: 0.757 AC: 22605 AN: 29866

GnomAD4 genome AF: 0.726 AC: 110475 AN: 152164 Hom.: 40603 Cov.: 34 AF XY: 0.732 AC XY: 54421 AN XY: 74396

African (AFR) AF: 0.606 AC: 25149 AN: 41482

American (AMR) AF: 0.807 AC: 12338 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2809 AN: 3468

East Asian (EAS) AF: 0.870 AC: 4500 AN: 5170

South Asian (SAS) AF: 0.719 AC: 3470 AN: 4828

European-Finnish (FIN) AF: 0.781 AC: 8278 AN: 10604

Middle Eastern (MID) AF: 0.784 AC: 229 AN: 292

European-Non Finnish (NFE) AF: 0.756 AC: 51380 AN: 68004

Other (OTH) AF: 0.760 AC: 1605 AN: 2112

Alfa AF: 0.754 Hom.: 42076

Bravo AF: 0.727

Asia WGS AF: 0.803 AC: 2794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11335891) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.31
PhyloP100		-0.33
PromoterAI		-0.16	Neutral
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: rs705381; hg19: chr7-94953949;