11-116836141-C-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_001425093.1(APOA1):c.427-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
APOA1
NM_001425093.1 splice_acceptor, intron
NM_001425093.1 splice_acceptor, intron
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 4.54
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 Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5125165 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.471G>C | p.Lys157Asn | missense_variant | 4/4 | ENST00000236850.5 | NP_000030.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOA1 | ENST00000236850.5 | c.471G>C | p.Lys157Asn | missense_variant | 4/4 | 1 | NM_000039.3 | ENSP00000236850.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460880Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726780
GnomAD4 exome
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1
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1460880
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32
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1
AN XY:
726780
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 12, 2023 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 157 of the APOA1 protein (p.Lys157Asn). This variant is not present in population databases (gnomAD no frequency). 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. 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 not expected to disrupt APOA1 protein function. This variant has not been reported in the literature in individuals affected with APOA1-related conditions. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2024 | The p.K157N variant (also known as c.471G>C), located in coding exon 3 of the APOA1 gene, results from a G to C substitution at nucleotide position 471. The lysine at codon 157 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;.;T;.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;D;T;T
Polyphen
P;P;.;P;P
Vest4
MutPred
Loss of ubiquitination at K157 (P = 0.0039);Loss of ubiquitination at K157 (P = 0.0039);.;Loss of ubiquitination at K157 (P = 0.0039);Loss of ubiquitination at K157 (P = 0.0039);
MVP
MPC
1.7
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at