rs121912722
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000039.3(APOA1):āc.566C>Gā(p.Pro189Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000436 in 1,604,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
APOA1
NM_000039.3 missense
NM_000039.3 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 5.19
Genes affected
APOA1 (HGNC:600): (apolipoprotein A1) This gene encodes apolipoprotein A-I, which is the major protein component of high density lipoprotein (HDL) in plasma. The encoded preproprotein is proteolytically processed to generate the mature protein, which promotes cholesterol efflux from tissues to the liver for excretion, and is a cofactor for lecithin cholesterolacyltransferase (LCAT), an enzyme responsible for the formation of most plasma cholesteryl esters. This gene is closely linked with two other apolipoprotein genes on chromosome 11. Defects in this gene are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.919
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.566C>G | p.Pro189Arg | missense_variant | Exon 4 of 4 | ENST00000236850.5 | NP_000030.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000418 AC: 1AN: 239404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131102
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GnomAD4 exome AF: 0.00000413 AC: 6AN: 1452430Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2AN XY: 722440
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Apolipoprotein A-I deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1989 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 189 of the APOA1 protein (p.Pro189Arg). This variant is present in population databases (rs121912722, gnomAD 0.0009%). This missense change has been observed in individual(s) with apolipoprotein A1 deficiency and/or low HDL-C (PMID: 2512329, 28870971). This variant is also known as Pro165Arg. ClinVar contains an entry for this variant (Variation ID: 17916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOA1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;.;T;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;.;D;D
Vest4
MutPred
Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);.;Gain of MoRF binding (P = 9e-04);Gain of MoRF binding (P = 9e-04);
MVP
MPC
1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at