7-95359943-CTTTTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr7-95359943-C-CTTTTTTTTTT
• rs76171675
• NM_000940.3:c.*20_*29dupAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000940.3(PON3):​c.*20_*29dupAAAAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000301 in 1,327,074 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000030 (1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*20_*29dupAAAAAAAAAA		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.*20_*29dupAAAAAAAAAA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000427422.5	TSL:3	c.*136_*145dupAAAAAAAAAA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
	PON3	ENST00000902762.1		c.*20_*29dupAAAAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000301 AC: 4 AN: 1327074 Hom.: 1 Cov.: 0 AF XY: 0.00000452 AC XY: 3 AN XY: 663124

African (AFR) AF: 0.0000346 AC: 1 AN: 28922

American (AMR) AF: 0.0000529 AC: 2 AN: 37840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24392

East Asian (EAS) AF: 0.00 AC: 0 AN: 37516

South Asian (SAS) AF: 0.00 AC: 0 AN: 77034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 9.83e-7 AC: 1 AN: 1017176

Other (OTH) AF: 0.00 AC: 0 AN: 55562

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38

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;