7-95315903-T-G

Variant names:

• chr7-95315903-T-G
• rs854557
• NM_000446.7:c.202-413A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.202-413A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,944 control chromosomes in the GnomAD database, including 7,028 homozygotes. 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 0.29 (7028 hom., cov: 32)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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.202-413A>C		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.202-413A>C		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.202-422A>C		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.202-413A>C		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43690 AN: 151828 Hom.: 7025 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.288 AC: 43702 AN: 151944 Hom.: 7028 Cov.: 32 AF XY: 0.284 AC XY: 21098 AN XY: 74256

African (AFR) AF: 0.176 AC: 7302 AN: 41448

American (AMR) AF: 0.274 AC: 4176 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1376 AN: 3468

East Asian (EAS) AF: 0.0359 AC: 186 AN: 5174

South Asian (SAS) AF: 0.202 AC: 974 AN: 4810

European-Finnish (FIN) AF: 0.351 AC: 3694 AN: 10528

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24885 AN: 67942

Other (OTH) AF: 0.317 AC: 668 AN: 2104

Alfa AF: 0.338 Hom.: 12815

Bravo AF: 0.278

Asia WGS AF: 0.118 AC: 415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.84
DANN	Benign	0.77
PhyloP100		-0.43
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: rs854557; hg19: chr7-94945215;