chr7-95394734-A-G

Variant names:

• chr7-95394734-A-G
• rs11970910
• NM_000940.3:c.75-20T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000940.3(PON3):​c.75-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,608,082 control chromosomes in the GnomAD database, including 203,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20701 hom., cov: 31)
  • Exomes 𝑓: 0.49 (182631 hom.)
• Consequence: PON3 NM_000940.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.19
• Publications: 15 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 -16 ACMG points.

• BP6: Variant 7-95394734-A-G is Benign according to our data. Variant chr7-95394734-A-G is described in ClinVar as Benign. ClinVar VariationId is 1252233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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.75-20T>C		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.75-20T>C		intron	N/A	ENSP00000265627.5
	PON3	ENST00000902762.1		c.75-20T>C		intron	N/A	ENSP00000572821.1
	PON3	ENST00000902763.1		c.75-20T>C		intron	N/A	ENSP00000572822.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78353 AN: 151894 Hom.: 20663 Cov.: 31

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.492

GnomAD2 exomes AF: 0.548 AC: 137755 AN: 251222 AF XY: 0.546

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.494 AC: 718820 AN: 1456070 Hom.: 182631 Cov.: 31 AF XY: 0.497 AC XY: 359968 AN XY: 724758

African (AFR) AF: 0.532 AC: 17761 AN: 33362

American (AMR) AF: 0.655 AC: 29267 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10431 AN: 26084

East Asian (EAS) AF: 0.798 AC: 31671 AN: 39676

South Asian (SAS) AF: 0.632 AC: 54449 AN: 86152

European-Finnish (FIN) AF: 0.596 AC: 31825 AN: 53376

Middle Eastern (MID) AF: 0.436 AC: 2514 AN: 5762

European-Non Finnish (NFE) AF: 0.461 AC: 510719 AN: 1106764

Other (OTH) AF: 0.502 AC: 30183 AN: 60182

GnomAD4 genome AF: 0.516 AC: 78452 AN: 152012 Hom.: 20701 Cov.: 31 AF XY: 0.530 AC XY: 39396 AN XY: 74336

African (AFR) AF: 0.522 AC: 21599 AN: 41416

American (AMR) AF: 0.581 AC: 8887 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1427 AN: 3466

East Asian (EAS) AF: 0.761 AC: 3935 AN: 5168

South Asian (SAS) AF: 0.642 AC: 3086 AN: 4806

European-Finnish (FIN) AF: 0.620 AC: 6565 AN: 10582

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31218 AN: 67972

Other (OTH) AF: 0.497 AC: 1048 AN: 2108

Alfa AF: 0.474 Hom.: 25485

Bravo AF: 0.514

Asia WGS AF: 0.703 AC: 2442 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
AlphaMissense	Uncertain	0.36
BayesDel_noAF	Benign	-0.81
CADD	Benign	15
DANN	Benign	0.53
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11970910; hg19: chr7-95024046; COSMIC: COSV55698508;