chr7-95367601-T-G

Variant names:

• chr7-95367601-T-G
• rs3757708
• NM_000940.3:c.368-113A>C

Variant summary

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

Score: -20 - Benign

-20

BP4_StrongBP6_Very_StrongBA1

The NM_000940.3(PON3):​c.368-113A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,143,818 control chromosomes in the GnomAD database, including 151,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21846 hom., cov: 32)
  • Exomes 𝑓: 0.50 (129744 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504
• Publications: 10 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=-0.89).
• BP6: Variant 7-95367601-T-G is Benign according to our data. Variant chr7-95367601-T-G is described in ClinVar as [Benign]. Clinvar id is 1221645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON3	NM_000940.3	c.368-113A>C		intron_variant	Intron 4 of 8	ENST00000265627.10	NP_000931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON3	ENST00000265627.10	c.368-113A>C		intron_variant	Intron 4 of 8	1	NM_000940.3	ENSP00000265627.5

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80472 AN: 151934 Hom.: 21797 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.504 AC: 499965 AN: 991766 Hom.: 129744 AF XY: 0.507 AC XY: 259327 AN XY: 511286

African (AFR) AF: 0.580 AC: 14016 AN: 24146

American (AMR) AF: 0.654 AC: 25823 AN: 39468

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 9024 AN: 22562

East Asian (EAS) AF: 0.808 AC: 29463 AN: 36456

South Asian (SAS) AF: 0.630 AC: 46912 AN: 74432

European-Finnish (FIN) AF: 0.591 AC: 23675 AN: 40054

Middle Eastern (MID) AF: 0.443 AC: 1409 AN: 3182

European-Non Finnish (NFE) AF: 0.463 AC: 327099 AN: 707020

Other (OTH) AF: 0.507 AC: 22544 AN: 44446

GnomAD4 genome AF: 0.530 AC: 80578 AN: 152052 Hom.: 21846 Cov.: 32 AF XY: 0.544 AC XY: 40401 AN XY: 74324

African (AFR) AF: 0.571 AC: 23662 AN: 41464

American (AMR) AF: 0.585 AC: 8922 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.767 AC: 3965 AN: 5168

South Asian (SAS) AF: 0.642 AC: 3091 AN: 4816

European-Finnish (FIN) AF: 0.620 AC: 6557 AN: 10582

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31187 AN: 67982

Other (OTH) AF: 0.509 AC: 1075 AN: 2110

Alfa AF: 0.479 Hom.: 25883

Bravo AF: 0.529

Asia WGS AF: 0.709 AC: 2463 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.40
PhyloP100		0.50
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: rs3757708; hg19: chr7-94996913; COSMIC: COSV55702730; COSMIC: COSV55702730;