rs201745303

Variant names:

• chr7-95360006-G-A
• rs201745303
• NM_000940.3:c.1032C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-95360006-G-A
• chr7-95360006-G-C
• chr7-95360006-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000940.3(PON3):​c.1032C>T​(p.Thr344Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0007 in 1,611,246 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (7 hom.)
• Consequence: PON3 NM_000940.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.89
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 7-95360006-G-A is Benign according to our data. Variant chr7-95360006-G-A is described in ClinVar as Benign. ClinVar VariationId is 756300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.89 with no splicing effect.
• BS2: High AC in GnomAd4 at 61 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	NM_000940.3	MANE Select	c.1032C>T	p.Thr344Thr	synonymous	Exon 9 of 9	NP_000931.1	Q15166

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	ENST00000265627.10	TSL:1 MANE Select	c.1032C>T	p.Thr344Thr	synonymous	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000902762.1		c.1215C>T	p.Thr405Thr	synonymous	Exon 10 of 10	ENSP00000572821.1
	PON3	ENST00000902763.1		c.1185C>T	p.Thr395Thr	synonymous	Exon 10 of 10	ENSP00000572822.1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 61 AN: 149622 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000868

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00504

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00194

GnomAD2 exomes AF: 0.00135 AC: 340 AN: 251262 AF XY: 0.00179

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000730 AC: 1067 AN: 1461504 Hom.: 7 Cov.: 36 AF XY: 0.000977 AC XY: 710 AN XY: 727070

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00857 AC: 739 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5766

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111756

Other (OTH) AF: 0.00118 AC: 71 AN: 60382

GnomAD4 genome AF: 0.000407 AC: 61 AN: 149742 Hom.: 1 Cov.: 32 AF XY: 0.000411 AC XY: 30 AN XY: 72934

African (AFR) AF: 0.0000247 AC: 1 AN: 40472

American (AMR) AF: 0.000867 AC: 13 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5068

South Asian (SAS) AF: 0.00505 AC: 24 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9986

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.000222 AC: 15 AN: 67712

Other (OTH) AF: 0.00192 AC: 4 AN: 2086

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000374

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

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	-0.71
CADD	Benign	2.4
DANN	Benign	0.76
PhyloP100		-4.9
Mutation Taster		=100/0	polymorphism

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: rs201745303; hg19: chr7-94989318; COSMIC: COSV104548960; COSMIC: COSV104548960;