chr7-95298396-T-C

Variant names:

• chr7-95298396-T-C
• rs3917577
• NM_000446.7:c.*548A>G

Variant summary

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

The NM_000446.7(PON1):​c.*548A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 165,540 control chromosomes in the GnomAD database, including 1,376 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 0.11 (1195 hom., cov: 32)
  • Exomes 𝑓: 0.13 (181 hom.)
• Consequence: PON1 NM_000446.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• Publications: 13 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 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.*548A>G		3_prime_UTR	Exon 9 of 9	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.*548A>G		3_prime_UTR	Exon 9 of 9	ENSP00000222381.3	P27169
	PON1	ENST00000893036.1		c.*548A>G		3_prime_UTR	Exon 9 of 9	ENSP00000563095.1
	PON1	ENST00000893037.1		c.*548A>G		3_prime_UTR	Exon 8 of 8	ENSP00000563096.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16324 AN: 152082 Hom.: 1196 Cov.: 32

Gnomad AFR AF: 0.0855

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0933

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.128 AC: 1704 AN: 13340 Hom.: 181 Cov.: 0 AF XY: 0.129 AC XY: 897 AN XY: 6980

African (AFR) AF: 0.0619 AC: 13 AN: 210

American (AMR) AF: 0.132 AC: 363 AN: 2740

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 20 AN: 172

East Asian (EAS) AF: 0.415 AC: 538 AN: 1296

South Asian (SAS) AF: 0.140 AC: 211 AN: 1512

European-Finnish (FIN) AF: 0.0417 AC: 7 AN: 168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 24

European-Non Finnish (NFE) AF: 0.0751 AC: 503 AN: 6696

Other (OTH) AF: 0.0939 AC: 49 AN: 522

GnomAD4 genome AF: 0.107 AC: 16332 AN: 152200 Hom.: 1195 Cov.: 32 AF XY: 0.110 AC XY: 8179 AN XY: 74410

African (AFR) AF: 0.0855 AC: 3550 AN: 41530

American (AMR) AF: 0.136 AC: 2076 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3472

East Asian (EAS) AF: 0.415 AC: 2142 AN: 5158

South Asian (SAS) AF: 0.158 AC: 760 AN: 4818

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10604

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0933 AC: 6347 AN: 68006

Other (OTH) AF: 0.134 AC: 284 AN: 2112

Alfa AF: 0.104 Hom.: 2655

Bravo AF: 0.115

Asia WGS AF: 0.282 AC: 979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.37
PhyloP100		-0.49
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: rs3917577; hg19: chr7-94927708;