rs17880470

chr7-95363949-A-Gchr7-95363949-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000940.3(PON3):c.609T>C(p.Tyr203=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,613,914 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (30 hom.)
• Consequence: PON3 NM_000940.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.158

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-95363949-A-G is Benign according to our data. Variant chr7-95363949-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 777175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PON3	NM_000940.3	c.609T>C	p.Tyr203=	synonymous_variant	6/9	ENST00000265627.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PON3	ENST00000265627.10	c.609T>C	p.Tyr203=	synonymous_variant	6/9	1	NM_000940.3	P1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00641

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00367 AC: 923 AN: 251256 Hom.: 3 AF XY: 0.00379 AC XY: 515 AN XY: 135772

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00535 AC: 7821 AN: 1461586 Hom.: 30 Cov.: 31 AF XY: 0.00539 AC XY: 3916 AN XY: 727104

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00652

Gnomad4 OTH exome AF: 0.00446

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74502

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00641

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00554 Hom.: 4

Bravo AF: 0.00380

EpiCase AF: 0.00398

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	PON3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.034
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17880470; hg19: chr7-94993261;