NM_000446.7:c.371-526C>T

Variant names:

• chr7-95312103-G-A
• rs3917521
• NM_000446.7:c.371-526C>T

Variant summary

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

The NM_000446.7(PON1):​c.371-526C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,154 control chromosomes in the GnomAD database, including 6,185 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 0.28 (6185 hom., cov: 33)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.371-526C>T		intron_variant	Intron 4 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.371-526C>T		intron_variant	Intron 4 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*96-526C>T		intron_variant	Intron 4 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.491-526C>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42158 AN: 152036 Hom.: 6163 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.277 AC: 42216 AN: 152154 Hom.: 6185 Cov.: 33 AF XY: 0.279 AC XY: 20743 AN XY: 74384

African (AFR) AF: 0.364 AC: 15117 AN: 41506

American (AMR) AF: 0.268 AC: 4096 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2603 AN: 5154

South Asian (SAS) AF: 0.265 AC: 1281 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2335 AN: 10574

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14971 AN: 68012

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.244 Hom.: 13313

Bravo AF: 0.286

Asia WGS AF: 0.406 AC: 1408 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		-0.075
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: rs3917521; hg19: chr7-94941415;