7-95359943-CTTTTTT-CTTTTTTTT

Variant names:

• chr7-95359943-C-CTT
• rs76171675
• NM_000940.3:c.*28_*29dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000940.3(PON3):​c.*28_*29dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00851 in 1,460,498 control chromosomes in the GnomAD database, including 112 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (105 hom., cov: 30)
  • Exomes 𝑓: 0.0064 (7 hom.)
• Consequence: PON3 NM_000940.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.382
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON3	NM_000940.3	MANE Select	c.*28_*29dupAA		3_prime_UTR	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.*28_*29dupAA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000427422.5	TSL:3	c.*144_*145dupAA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
	PON3	ENST00000902762.1		c.*28_*29dupAA		3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 3974 AN: 138290 Hom.: 104 Cov.: 30

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.00466

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00586

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0138

Gnomad NFE AF: 0.00834

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00902 AC: 1165 AN: 129166 AF XY: 0.00849

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00918

Gnomad ASJ exome AF: 0.00571

Gnomad EAS exome AF: 0.00904

Gnomad FIN exome AF: 0.00901

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00639 AC: 8443 AN: 1322182 Hom.: 7 Cov.: 0 AF XY: 0.00642 AC XY: 4239 AN XY: 660648

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0377 AC: 1078 AN: 28560

American (AMR) AF: 0.00762 AC: 287 AN: 37674

Ashkenazi Jewish (ASJ) AF: 0.00424 AC: 103 AN: 24318

East Asian (EAS) AF: 0.0166 AC: 617 AN: 37224

South Asian (SAS) AF: 0.0110 AC: 840 AN: 76442

European-Finnish (FIN) AF: 0.0109 AC: 470 AN: 43232

Middle Eastern (MID) AF: 0.00603 AC: 31 AN: 5144

European-Non Finnish (NFE) AF: 0.00446 AC: 4528 AN: 1014318

Other (OTH) AF: 0.00885 AC: 489 AN: 55270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0288 AC: 3984 AN: 138316 Hom.: 105 Cov.: 30 AF XY: 0.0293 AC XY: 1956 AN XY: 66826

African (AFR) AF: 0.0701 AC: 2664 AN: 37986

American (AMR) AF: 0.0206 AC: 282 AN: 13668

Ashkenazi Jewish (ASJ) AF: 0.00586 AC: 19 AN: 3240

East Asian (EAS) AF: 0.0218 AC: 105 AN: 4812

South Asian (SAS) AF: 0.0228 AC: 98 AN: 4292

European-Finnish (FIN) AF: 0.0294 AC: 240 AN: 8164

Middle Eastern (MID) AF: 0.0152 AC: 4 AN: 264

European-Non Finnish (NFE) AF: 0.00834 AC: 527 AN: 63158

Other (OTH) AF: 0.0219 AC: 41 AN: 1874

Alfa AF: 0.00390 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs76171675; hg19: chr7-94989255;