NM_000446.7:c.145+729C>T

Variant names:

• chr7-95317594-G-A
• rs28699500
• NM_000446.7:c.145+729C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000446.7(PON1):​c.145+729C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (4941 hom., cov: 10)
  • Failed GnomAD Quality Control
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• Publications: 3 publications found

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

PON1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. 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
	PON1	NM_000446.7	MANE Select	c.145+729C>T		intron	N/A	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.145+729C>T		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.145+729C>T		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.145+729C>T		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 33334 AN: 72096 Hom.: 4938 Cov.: 10

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.492

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.474

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.462 AC: 33341 AN: 72100 Hom.: 4941 Cov.: 10 AF XY: 0.465 AC XY: 16154 AN XY: 34706

African (AFR) AF: 0.419 AC: 8356 AN: 19926

American (AMR) AF: 0.506 AC: 3771 AN: 7452

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 959 AN: 1842

East Asian (EAS) AF: 0.624 AC: 2521 AN: 4040

South Asian (SAS) AF: 0.452 AC: 1255 AN: 2774

European-Finnish (FIN) AF: 0.393 AC: 969 AN: 2466

Middle Eastern (MID) AF: 0.482 AC: 54 AN: 112

European-Non Finnish (NFE) AF: 0.462 AC: 14850 AN: 32150

Other (OTH) AF: 0.477 AC: 488 AN: 1024

Alfa AF: 0.606 Hom.: 3432

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.57
DANN	Benign	0.23
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28699500; hg19: chr7-94946906;