7-95316772-A-T

Variant names:

• chr7-95316772-A-T
• rs854560
• NM_000446.7:c.163T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000446.7(PON1):​c.163T>A​(p.Leu55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,611,280 control chromosomes in the GnomAD database, including 93,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7008 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86372 hom.)
• Consequence: PON1 NM_000446.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.197
• Publications: 702 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028376877).
• BP6: Variant 7-95316772-A-T is Benign according to our data. Variant chr7-95316772-A-T is described in ClinVar as Benign. ClinVar VariationId is 13736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.163T>A	p.Leu55Met	missense	Exon 3 of 9	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.163T>A	p.Leu55Met	missense	Exon 3 of 9	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.163T>A		non_coding_transcript_exon	Exon 3 of 9	ENSP00000407359.1
	PON1	ENST00000470502.1	TSL:4	n.283T>A		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43605 AN: 151866 Hom.: 7006 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.289 AC: 72592 AN: 251376 AF XY: 0.294

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.0347

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.335 AC: 488902 AN: 1459296 Hom.: 86372 Cov.: 33 AF XY: 0.333 AC XY: 241873 AN XY: 726094

African (AFR) AF: 0.168 AC: 5610 AN: 33432

American (AMR) AF: 0.209 AC: 9360 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10434 AN: 26108

East Asian (EAS) AF: 0.0589 AC: 2338 AN: 39664

South Asian (SAS) AF: 0.210 AC: 18115 AN: 86214

European-Finnish (FIN) AF: 0.361 AC: 19265 AN: 53416

Middle Eastern (MID) AF: 0.383 AC: 2207 AN: 5760

European-Non Finnish (NFE) AF: 0.362 AC: 402083 AN: 1109662

Other (OTH) AF: 0.323 AC: 19490 AN: 60322

GnomAD4 genome AF: 0.287 AC: 43616 AN: 151984 Hom.: 7008 Cov.: 32 AF XY: 0.284 AC XY: 21050 AN XY: 74240

African (AFR) AF: 0.175 AC: 7244 AN: 41454

American (AMR) AF: 0.273 AC: 4173 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1377 AN: 3466

East Asian (EAS) AF: 0.0360 AC: 186 AN: 5170

South Asian (SAS) AF: 0.202 AC: 971 AN: 4814

European-Finnish (FIN) AF: 0.351 AC: 3691 AN: 10526

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

European-Non Finnish (NFE) AF: 0.366 AC: 24867 AN: 67946

Other (OTH) AF: 0.315 AC: 666 AN: 2114

Alfa AF: 0.349 Hom.: 7322

Bravo AF: 0.277

TwinsUK AF: 0.369 AC: 1369

ALSPAC AF: 0.363 AC: 1398

ESP6500AA AF: 0.173 AC: 762

ESP6500EA AF: 0.373 AC: 3208

ExAC AF: 0.291 AC: 35356

Asia WGS AF: 0.118 AC: 413 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.366

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23590198, 23538572, 26241956, 9011577, 21718208, 21231776, 20390392, 21229382, 12867538, 21783258, 20812194, 19269283, 18708400, 10952224, 20042177, 23007074)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

PON1-related disorder Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Enzyme activity finding Other:1

Jun 09, 2025

OMIM

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.20
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.064
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0040	B
Vest4		0.11
MPC		0.16
ClinPred		0.041	T
GERP RS		-1.8
Varity_R		0.14
gMVP		0.81
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs854560; hg19: chr7-94946084; COSMIC: COSV55932359;