7-95362320-T-C

Variant names:

• chr7-95362320-T-C
• rs17884000
• NM_000940.3:c.906+42A>G

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.906+42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,610,854 control chromosomes in the GnomAD database, including 41,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3576 hom., cov: 33)
  • Exomes 𝑓: 0.21 (38416 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0110
• Publications: 9 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=-0.85).
• BP6: Variant 7-95362320-T-C is Benign according to our data. Variant chr7-95362320-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 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.906+42A>G		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.906+42A>G		intron	N/A	ENSP00000265627.5
	PON3	ENST00000451904.5	TSL:3	c.*41+42A>G		intron	N/A	ENSP00000403850.1
	PON3	ENST00000427422.5	TSL:3	c.695+1543A>G		intron	N/A	ENSP00000413276.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28039 AN: 152096 Hom.: 3574 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.253 AC: 63059 AN: 249484 AF XY: 0.246

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.605

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.212 AC: 309703 AN: 1458640 Hom.: 38416 Cov.: 33 AF XY: 0.212 AC XY: 153789 AN XY: 725778

African (AFR) AF: 0.0536 AC: 1792 AN: 33430

American (AMR) AF: 0.424 AC: 18904 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 5473 AN: 26082

East Asian (EAS) AF: 0.614 AC: 24355 AN: 39658

South Asian (SAS) AF: 0.235 AC: 20208 AN: 86170

European-Finnish (FIN) AF: 0.155 AC: 8284 AN: 53276

Middle Eastern (MID) AF: 0.174 AC: 1000 AN: 5758

European-Non Finnish (NFE) AF: 0.195 AC: 216608 AN: 1109416

Other (OTH) AF: 0.217 AC: 13079 AN: 60282

GnomAD4 genome AF: 0.184 AC: 28045 AN: 152214 Hom.: 3576 Cov.: 33 AF XY: 0.190 AC XY: 14165 AN XY: 74422

African (AFR) AF: 0.0652 AC: 2711 AN: 41568

American (AMR) AF: 0.329 AC: 5028 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3472

East Asian (EAS) AF: 0.591 AC: 3054 AN: 5166

South Asian (SAS) AF: 0.254 AC: 1225 AN: 4816

European-Finnish (FIN) AF: 0.155 AC: 1643 AN: 10614

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13029 AN: 67978

Other (OTH) AF: 0.204 AC: 431 AN: 2110

Alfa AF: 0.203 Hom.: 4122

Bravo AF: 0.197

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.63
PhyloP100		-0.011
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: rs17884000; hg19: chr7-94991632; COSMIC: COSV55698528; COSMIC: COSV55698528;