7-95372046-A-T

Variant names:

• chr7-95372046-A-T
• rs2375002
• NM_000940.3:c.367+127T>A

Variant summary

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

The NM_000940.3(PON3):​c.367+127T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,060,028 control chromosomes in the GnomAD database, including 466,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68652 hom., cov: 30)
  • Exomes 𝑓: 0.94 (397813 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780
• Publications: 2 publications found

Genes affected

PON3 (HGNC:9206): (paraoxonase 3) This gene is a member of the paraoxonase family and lies in a cluster on chromosome 7 with the other two family members. The encoded protein is secreted into the bloodstream and associates with high-density lipoprotein (HDL). The protein also rapidly hydrolyzes lactones and can inhibit the oxidation of low-density lipoprotein (LDL), a function that is believed to slow the initiation and progression of atherosclerosis. Alternatively spliced variants which encode different protein isoforms have been described; however, only one has been fully characterized. [provided by RefSeq, Jul 2008]

PON3 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=-0.95).
• BP6: Variant 7-95372046-A-T is Benign according to our data. Variant chr7-95372046-A-T is described in ClinVar as Benign. ClinVar VariationId is 1294630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000940.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	NM_000940.3	MANE Select	c.367+127T>A		intron	N/A	NP_000931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.367+127T>A		intron	N/A	ENSP00000265627.5
	PON3	ENST00000451904.5	TSL:3	c.367+127T>A		intron	N/A	ENSP00000403850.1
	PON3	ENST00000427422.5	TSL:3	c.367+127T>A		intron	N/A	ENSP00000413276.1

Frequencies

GnomAD3 genomes AF: 0.949 AC: 144263 AN: 151966 Hom.: 68593 Cov.: 30

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.953

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.959

GnomAD4 exome AF: 0.936 AC: 849426 AN: 907942 Hom.: 397813 AF XY: 0.936 AC XY: 440217 AN XY: 470280

African (AFR) AF: 0.980 AC: 20693 AN: 21114

American (AMR) AF: 0.978 AC: 34289 AN: 35074

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 20117 AN: 21302

East Asian (EAS) AF: 0.840 AC: 29453 AN: 35078

South Asian (SAS) AF: 0.945 AC: 65007 AN: 68794

European-Finnish (FIN) AF: 0.935 AC: 41364 AN: 44236

Middle Eastern (MID) AF: 0.951 AC: 3025 AN: 3182

European-Non Finnish (NFE) AF: 0.936 AC: 596630 AN: 637758

Other (OTH) AF: 0.938 AC: 38848 AN: 41404

GnomAD4 genome AF: 0.949 AC: 144382 AN: 152086 Hom.: 68652 Cov.: 30 AF XY: 0.949 AC XY: 70559 AN XY: 74338

African (AFR) AF: 0.979 AC: 40660 AN: 41518

American (AMR) AF: 0.973 AC: 14846 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3295 AN: 3468

East Asian (EAS) AF: 0.816 AC: 4208 AN: 5160

South Asian (SAS) AF: 0.944 AC: 4537 AN: 4808

European-Finnish (FIN) AF: 0.942 AC: 9977 AN: 10588

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.937 AC: 63683 AN: 67970

Other (OTH) AF: 0.959 AC: 2023 AN: 2110

Alfa AF: 0.940 Hom.: 8358

Bravo AF: 0.952

Asia WGS AF: 0.879 AC: 3059 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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		0.078
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: rs2375002; hg19: chr7-95001358;