7-95359943-CTTTTTT-CTTTTT

Variant names:

• chr7-95359943-CT-C
• rs76171675
• NM_000940.3:c.*29delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000940.3(PON3):​c.*29delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 138,192 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0090 (3 hom., cov: 30)
  • Exomes 𝑓: 0.34 (1 hom.)
  • Failed GnomAD Quality Control
• 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.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00896 (1238/138192) while in subpopulation SAS AF = 0.0261 (112/4292). AF 95% confidence interval is 0.0222. There are 3 homozygotes in GnomAd4. There are 670 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1238 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.*29delA		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.*29delA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000427422.5	TSL:3	c.*145delA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
	PON3	ENST00000902762.1		c.*29delA		3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes AF: 0.00891 AC: 1231 AN: 138168 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00309

Gnomad EAS AF: 0.00353

Gnomad SAS AF: 0.0256

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00814

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.410 AC: 53004 AN: 129166 AF XY: 0.412

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.418

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.345 AC: 409452 AN: 1187342 Hom.: 1 Cov.: 0 AF XY: 0.347 AC XY: 205572 AN XY: 592028

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

African (AFR) AF: 0.295 AC: 7816 AN: 26514

American (AMR) AF: 0.331 AC: 11513 AN: 34820

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 7814 AN: 21576

East Asian (EAS) AF: 0.350 AC: 11977 AN: 34210

South Asian (SAS) AF: 0.341 AC: 23474 AN: 68748

European-Finnish (FIN) AF: 0.306 AC: 12207 AN: 39940

Middle Eastern (MID) AF: 0.348 AC: 1651 AN: 4740

European-Non Finnish (NFE) AF: 0.348 AC: 315693 AN: 906804

Other (OTH) AF: 0.346 AC: 17307 AN: 49990

⚠️ 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: 0.00896 AC: 1238 AN: 138192 Hom.: 3 Cov.: 30 AF XY: 0.0100 AC XY: 670 AN XY: 66750

African (AFR) AF: 0.00637 AC: 242 AN: 38004

American (AMR) AF: 0.00865 AC: 118 AN: 13648

Ashkenazi Jewish (ASJ) AF: 0.00309 AC: 10 AN: 3238

East Asian (EAS) AF: 0.00375 AC: 18 AN: 4804

South Asian (SAS) AF: 0.0261 AC: 112 AN: 4292

European-Finnish (FIN) AF: 0.0250 AC: 203 AN: 8106

Middle Eastern (MID) AF: 0.0114 AC: 3 AN: 264

European-Non Finnish (NFE) AF: 0.00815 AC: 514 AN: 63106

Other (OTH) AF: 0.00962 AC: 18 AN: 1872

Alfa AF: 0.105 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 (auto)

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: COSV55699602; COSMIC: COSV55699602;