7-95363949-A-G

Variant names:

• chr7-95363949-A-G
• rs17880470
• NM_000940.3:c.609T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000265627.10(PON3):​c.609T>C​(p.Tyr203Tyr) 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 ENST00000265627.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.158
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 777175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 531 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265627.10. 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.609T>C	p.Tyr203Tyr	synonymous	Exon 6 of 9	NP_000931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.609T>C	p.Tyr203Tyr	synonymous	Exon 6 of 9	ENSP00000265627.5
	PON3	ENST00000451904.5	TSL:3	c.609T>C	p.Tyr203Tyr	synonymous	Exon 6 of 9	ENSP00000403850.1
	PON3	ENST00000427422.5	TSL:3	c.609T>C	p.Tyr203Tyr	synonymous	Exon 6 of 7	ENSP00000413276.1

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

GnomAD2 exomes AF: 0.00367 AC: 923 AN: 251256 AF XY: 0.00379

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 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

African (AFR) AF: 0.000926 AC: 31 AN: 33462

American (AMR) AF: 0.00210 AC: 94 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00134 AC: 116 AN: 86250

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53420

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00652 AC: 7247 AN: 1111778

Other (OTH) AF: 0.00446 AC: 269 AN: 60376

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

African (AFR) AF: 0.000962 AC: 40 AN: 41574

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00641 AC: 436 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00516 Hom.: 6

Bravo AF: 0.00380

EpiCase AF: 0.00398

EpiControl AF: 0.00522

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.034
DANN	Benign	0.64
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17880470; hg19: chr7-94993261;