7-95302075-C-T

Variant names:

• chr7-95302075-C-T
• rs7809060
• NM_000446.7:c.909+130G>A

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.909+130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 923,172 control chromosomes in the GnomAD database, including 3,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (667 hom., cov: 21)
  • Exomes 𝑓: 0.056 (2523 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27
• Publications: 2 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=-1.02).
• BP6: Variant 7-95302075-C-T is Benign according to our data. Variant chr7-95302075-C-T is described in ClinVar as [Benign]. Clinvar id is 1228238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.909+130G>A		intron_variant	Intron 8 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.909+130G>A		intron_variant	Intron 8 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*634+130G>A		intron_variant	Intron 8 of 8	3		ENSP00000407359.1
PON1	ENST00000462594.1	n.199+130G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.100 AC: 11687 AN: 116622 Hom.: 666 Cov.: 21

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0676

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.164

Gnomad NFE AF: 0.0614

Gnomad OTH AF: 0.0832

GnomAD4 exome AF: 0.0564 AC: 45474 AN: 806522 Hom.: 2523 AF XY: 0.0577 AC XY: 23838 AN XY: 413356

African (AFR) AF: 0.141 AC: 2501 AN: 17742

American (AMR) AF: 0.0686 AC: 1602 AN: 23354

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 1123 AN: 16954

East Asian (EAS) AF: 0.0281 AC: 694 AN: 24718

South Asian (SAS) AF: 0.0813 AC: 4492 AN: 55254

European-Finnish (FIN) AF: 0.0696 AC: 1882 AN: 27028

Middle Eastern (MID) AF: 0.0608 AC: 159 AN: 2616

European-Non Finnish (NFE) AF: 0.0513 AC: 30902 AN: 602882

Other (OTH) AF: 0.0589 AC: 2119 AN: 35974

GnomAD4 genome AF: 0.100 AC: 11702 AN: 116650 Hom.: 667 Cov.: 21 AF XY: 0.106 AC XY: 5691 AN XY: 53656

African (AFR) AF: 0.183 AC: 5552 AN: 30282

American (AMR) AF: 0.105 AC: 896 AN: 8544

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 217 AN: 3210

East Asian (EAS) AF: 0.0418 AC: 127 AN: 3038

South Asian (SAS) AF: 0.0992 AC: 344 AN: 3466

European-Finnish (FIN) AF: 0.135 AC: 643 AN: 4754

Middle Eastern (MID) AF: 0.169 AC: 22 AN: 130

European-Non Finnish (NFE) AF: 0.0614 AC: 3739 AN: 60876

Other (OTH) AF: 0.0829 AC: 125 AN: 1508

Alfa AF: 0.0188 Hom.: 12

Bravo AF: 0.0867

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 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.80
PhyloP100		-1.3
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: rs7809060; hg19: chr7-94931387;