rs121912722

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000039.3(APOA1):ā€‹c.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

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.19
Variant links:
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]

Genome browser will be placed here

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
APOA1NM_000039.3 linkc.566C>G p.Pro189Arg missense_variant Exon 4 of 4 ENST00000236850.5 NP_000030.1 P02647A0A024R3E3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOA1ENST00000236850.5 linkc.566C>G p.Pro189Arg missense_variant Exon 4 of 4 1 NM_000039.3 ENSP00000236850.3 P02647

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000418
AC:
1
AN:
239404
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131102
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000920
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000413
AC:
6
AN:
1452430
Hom.:
0
Cov.:
32
AF XY:
0.00000277
AC XY:
2
AN XY:
722440
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000303
Hom.:
0
Bravo
AF:
0.00000756

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 providedliterature onlyOMIMDec 01, 1989- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;T;T;T;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
.;.;T;.;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Uncertain
2.9
M;M;.;M;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-8.3
D;D;D;D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0020
D;D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D;D
Polyphen
1.0
D;D;.;D;D
Vest4
0.81
MutPred
0.57
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
0.99
MPC
1.6
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.97
gMVP
0.69

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: rs121912722; hg19: chr11-116706762; API