chr7-95359943-CTTT-C

Variant names:

• chr7-95359943-CTTT-C
• rs76171675
• NM_000940.3:c.*27_*29delAAA

Variant summary

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

The NM_000940.3(PON3):​c.*27_*29delAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,311,276 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (0 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: 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.*27_*29delAAA		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.*27_*29delAAA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000451904.5	TSL:3	c.*227_*229delAAA		splice_region	Exon 9 of 9	ENSP00000403850.1	F8WD41
	PON3	ENST00000427422.5	TSL:3	c.*143_*145delAAA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 138332 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00198 AC: 256 AN: 129166 AF XY: 0.00188

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00107

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.000589

GnomAD4 exome AF: 0.00166 AC: 2179 AN: 1311276 Hom.: 0 AF XY: 0.00162 AC XY: 1065 AN XY: 655516

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

African (AFR) AF: 0.00140 AC: 40 AN: 28614

American (AMR) AF: 0.00205 AC: 77 AN: 37476

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 46 AN: 24090

East Asian (EAS) AF: 0.00137 AC: 51 AN: 37116

South Asian (SAS) AF: 0.00123 AC: 94 AN: 76396

European-Finnish (FIN) AF: 0.00205 AC: 88 AN: 42988

Middle Eastern (MID) AF: 0.00157 AC: 8 AN: 5098

European-Non Finnish (NFE) AF: 0.00167 AC: 1678 AN: 1004600

Other (OTH) AF: 0.00177 AC: 97 AN: 54898

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 138332 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 66810

African (AFR) AF: 0.00 AC: 0 AN: 37958

American (AMR) AF: 0.00 AC: 0 AN: 13652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3242

East Asian (EAS) AF: 0.00 AC: 0 AN: 4824

South Asian (SAS) AF: 0.00 AC: 0 AN: 4304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63178

Other (OTH) AF: 0.00 AC: 0 AN: 1866

Alfa AF: 0.00174 Hom.: 3

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;