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GeneBe

rs854560

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000446.7(PON1):c.163T>G(p.Leu55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L55M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PON1
NM_000446.7 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.197
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13520142).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PON1NM_000446.7 linkuse as main transcriptc.163T>G p.Leu55Val missense_variant 3/9 ENST00000222381.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PON1ENST00000222381.8 linkuse as main transcriptc.163T>G p.Leu55Val missense_variant 3/91 NM_000446.7 P1
PON1ENST00000470502.1 linkuse as main transcriptn.283T>G non_coding_transcript_exon_variant 2/44
PON1ENST00000433729.1 linkuse as main transcriptc.163T>G p.Leu55Val missense_variant, NMD_transcript_variant 3/93

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460752
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726782
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
Cadd
Benign
17
Dann
Uncertain
0.98
DEOGEN2
Benign
0.081
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.0096
T
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
0.55
D;D
PrimateAI
Benign
0.34
T
PROVEAN
Benign
0.42
N
REVEL
Benign
0.085
Sift
Benign
0.082
T
Sift4G
Uncertain
0.058
T
Polyphen
0.0
B
Vest4
0.17
MutPred
0.33
Loss of disorder (P = 0.1309);
MVP
0.26
MPC
0.15
ClinPred
0.59
D
GERP RS
-1.8
Varity_R
0.065
gMVP
0.82

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs854560; hg19: chr7-94946084; API