rs705379

Variant names:

• chr7-95324583-G-A
• rs705379
• NM_000446.7:c.-108C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-95324583-G-A
• chr7-95324583-G-C
• chr7-95324583-G-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.-108C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,123,462 control chromosomes in the GnomAD database, including 117,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12486 hom., cov: 32)
  • Exomes 𝑓: 0.46 (104557 hom.)
• Consequence: PON1 NM_000446.7 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13
• Publications: 261 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=-0.83).
• BP6: Variant 7-95324583-G-A is Benign according to our data. Variant chr7-95324583-G-A is described in ClinVar as Benign. ClinVar VariationId is 13737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.-108C>T		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.-108C>T		upstream_gene_variant		1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.-108C>T		upstream_gene_variant		3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56913 AN: 151920 Hom.: 12490 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.458 AC: 444754 AN: 971426 Hom.: 104557 Cov.: 13 AF XY: 0.458 AC XY: 227112 AN XY: 496168

African (AFR) AF: 0.126 AC: 2954 AN: 23360

American (AMR) AF: 0.457 AC: 16122 AN: 35284

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 13671 AN: 22392

East Asian (EAS) AF: 0.460 AC: 15586 AN: 33872

South Asian (SAS) AF: 0.401 AC: 28437 AN: 70844

European-Finnish (FIN) AF: 0.362 AC: 16125 AN: 44584

Middle Eastern (MID) AF: 0.490 AC: 2034 AN: 4148

European-Non Finnish (NFE) AF: 0.476 AC: 329845 AN: 692988

Other (OTH) AF: 0.455 AC: 19980 AN: 43954

GnomAD4 genome AF: 0.374 AC: 56917 AN: 152036 Hom.: 12486 Cov.: 32 AF XY: 0.373 AC XY: 27745 AN XY: 74304

African (AFR) AF: 0.138 AC: 5726 AN: 41536

American (AMR) AF: 0.472 AC: 7203 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2135 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2282 AN: 5140

South Asian (SAS) AF: 0.401 AC: 1928 AN: 4812

European-Finnish (FIN) AF: 0.346 AC: 3670 AN: 10592

Middle Eastern (MID) AF: 0.524 AC: 152 AN: 290

European-Non Finnish (NFE) AF: 0.480 AC: 32610 AN: 67912

Other (OTH) AF: 0.435 AC: 917 AN: 2106

Alfa AF: 0.394 Hom.: 2269

Bravo AF: 0.376

Asia WGS AF: 0.387 AC: 1348 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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: 26154629, 11335891, 10669651) -

Enzyme activity finding Benign:1

Jun 01, 2001

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.91
PhyloP100		-1.1
PromoterAI		-0.059	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: rs705379; hg19: chr7-94953895; COSMIC: COSV55931894; COSMIC: COSV55931894;