7-95359943-CTTTTTT-CTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000940.3(PON3):​c.*29dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,452,720 control chromosomes in the GnomAD database, including 179 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (162 hom., cov: 30)
  • Exomes 𝑓: 0.049 (17 hom.)
• Consequence: PON3 NM_000940.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 7-95359943-C-CT is Benign according to our data. Variant chr7-95359943-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1180951.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.061 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.*29dupA		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.*29dupA		3_prime_UTR	Exon 9 of 9	ENSP00000265627.5	Q15166
	PON3	ENST00000427422.5	TSL:3	c.*145dupA		splice_region	Exon 7 of 7	ENSP00000413276.1	C9JZ99
	PON3	ENST00000902762.1		c.*29dupA		3_prime_UTR	Exon 10 of 10	ENSP00000572821.1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 5938 AN: 138332 Hom.: 159 Cov.: 30

Gnomad AFR AF: 0.0628

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0194

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0562

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0489 AC: 6310 AN: 129166 AF XY: 0.0493

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.0387

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0494

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0491 AC: 64598 AN: 1314362 Hom.: 17 Cov.: 0 AF XY: 0.0486 AC XY: 31900 AN XY: 656778

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

African (AFR) AF: 0.0694 AC: 1981 AN: 28550

American (AMR) AF: 0.0444 AC: 1665 AN: 37518

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 803 AN: 24220

East Asian (EAS) AF: 0.0424 AC: 1575 AN: 37184

South Asian (SAS) AF: 0.0555 AC: 4212 AN: 75898

European-Finnish (FIN) AF: 0.0271 AC: 1173 AN: 43230

Middle Eastern (MID) AF: 0.0299 AC: 153 AN: 5114

European-Non Finnish (NFE) AF: 0.0500 AC: 50352 AN: 1007570

Other (OTH) AF: 0.0487 AC: 2684 AN: 55078

⚠️ 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: 0.0431 AC: 5960 AN: 138358 Hom.: 162 Cov.: 30 AF XY: 0.0420 AC XY: 2808 AN XY: 66852

African (AFR) AF: 0.0631 AC: 2400 AN: 38024

American (AMR) AF: 0.0479 AC: 654 AN: 13654

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 63 AN: 3242

East Asian (EAS) AF: 0.0281 AC: 135 AN: 4812

South Asian (SAS) AF: 0.0564 AC: 242 AN: 4294

European-Finnish (FIN) AF: 0.0181 AC: 148 AN: 8166

Middle Eastern (MID) AF: 0.0189 AC: 5 AN: 264

European-Non Finnish (NFE) AF: 0.0353 AC: 2233 AN: 63170

Other (OTH) AF: 0.0422 AC: 79 AN: 1874

Alfa AF: 0.0193 Hom.: 3

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;