7-95359943-CTTTTTT-CTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000940.3(PON3):​c.*28_*29delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,383,802 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 30)
  • Exomes 𝑓: 0.030 (0 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: Uncertain_significance. The variant received 0 ACMG points.

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_*29delAA		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_*29delAA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000427422.5	TSL:3	c.*144_*145delAA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
	PON3	ENST00000902762.1		c.*28_*29delAA		3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 51 AN: 138194 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000513

Gnomad ASJ AF: 0.000308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00222

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000269

Gnomad OTH AF: 0.00107

GnomAD2 exomes AF: 0.0358 AC: 4624 AN: 129166 AF XY: 0.0360

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.0396

Gnomad ASJ exome AF: 0.0371

Gnomad EAS exome AF: 0.0310

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0297 AC: 37029 AN: 1245582 Hom.: 0 AF XY: 0.0293 AC XY: 18251 AN XY: 622712

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

African (AFR) AF: 0.0267 AC: 729 AN: 27284

American (AMR) AF: 0.0346 AC: 1233 AN: 35658

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 819 AN: 22804

East Asian (EAS) AF: 0.0309 AC: 1092 AN: 35322

South Asian (SAS) AF: 0.0290 AC: 2110 AN: 72816

European-Finnish (FIN) AF: 0.0316 AC: 1296 AN: 40970

Middle Eastern (MID) AF: 0.0235 AC: 115 AN: 4894

European-Non Finnish (NFE) AF: 0.0294 AC: 28007 AN: 953724

Other (OTH) AF: 0.0312 AC: 1628 AN: 52110

⚠️ 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: 0.000376 AC: 52 AN: 138220 Hom.: 0 Cov.: 30 AF XY: 0.000344 AC XY: 23 AN XY: 66772

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

African (AFR) AF: 0.000158 AC: 6 AN: 38012

American (AMR) AF: 0.000513 AC: 7 AN: 13654

Ashkenazi Jewish (ASJ) AF: 0.000308 AC: 1 AN: 3242

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4812

South Asian (SAS) AF: 0.00 AC: 0 AN: 4292

European-Finnish (FIN) AF: 0.00222 AC: 18 AN: 8090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000269 AC: 17 AN: 63126

Other (OTH) AF: 0.00107 AC: 2 AN: 1872

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0171 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; COSMIC: COSV55701737;