chr7-95308312-G-A

Variant names:

• chr7-95308312-G-A
• rs3917541
• NM_000446.7:c.498-101C>T

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.498-101C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,098,950 control chromosomes in the GnomAD database, including 3,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (953 hom., cov: 32)
  • Exomes 𝑓: 0.067 (2790 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169
• Publications: 8 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=-0.86).
• BP6: Variant 7-95308312-G-A is Benign according to our data. Variant chr7-95308312-G-A is described in ClinVar as Benign. ClinVar VariationId is 1243112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.498-101C>T		intron_variant	Intron 5 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.498-101C>T		intron_variant	Intron 5 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*223-101C>T		intron_variant	Intron 5 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14546 AN: 152072 Hom.: 948 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0724

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0855

GnomAD4 exome AF: 0.0672 AC: 63634 AN: 946760 Hom.: 2790 AF XY: 0.0660 AC XY: 32202 AN XY: 488278

African (AFR) AF: 0.170 AC: 3822 AN: 22438

American (AMR) AF: 0.184 AC: 7138 AN: 38864

Ashkenazi Jewish (ASJ) AF: 0.0684 AC: 1554 AN: 22716

East Asian (EAS) AF: 0.115 AC: 3975 AN: 34560

South Asian (SAS) AF: 0.0674 AC: 4851 AN: 71966

European-Finnish (FIN) AF: 0.0663 AC: 2714 AN: 40928

Middle Eastern (MID) AF: 0.0692 AC: 251 AN: 3626

European-Non Finnish (NFE) AF: 0.0541 AC: 36134 AN: 668260

Other (OTH) AF: 0.0736 AC: 3195 AN: 43402

GnomAD4 genome AF: 0.0958 AC: 14574 AN: 152190 Hom.: 953 Cov.: 32 AF XY: 0.0963 AC XY: 7170 AN XY: 74426

African (AFR) AF: 0.168 AC: 6973 AN: 41498

American (AMR) AF: 0.126 AC: 1924 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3468

East Asian (EAS) AF: 0.118 AC: 613 AN: 5174

South Asian (SAS) AF: 0.0714 AC: 345 AN: 4832

European-Finnish (FIN) AF: 0.0689 AC: 730 AN: 10602

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0520 AC: 3536 AN: 68004

Other (OTH) AF: 0.0846 AC: 179 AN: 2116

Alfa AF: 0.0711 Hom.: 649

Bravo AF: 0.106

Asia WGS AF: 0.101 AC: 353 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 20, 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	-0.86
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		0.17
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: rs3917541; hg19: chr7-94937624;