11-116836141-C-G

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

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.54
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]
APOA1-AS (HGNC:40079): (APOA1 antisense RNA)

Genome browser will be placed here

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
APOA1NM_000039.3 linkuse as main transcriptc.471G>C p.Lys157Asn missense_variant 4/4 ENST00000236850.5 NP_000030.1 P02647A0A024R3E3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APOA1ENST00000236850.5 linkuse as main transcriptc.471G>C p.Lys157Asn missense_variant 4/41 NM_000039.3 ENSP00000236850.3 P02647

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460880
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726780
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 12, 2023This 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 submitterclinical testingAmbry GeneticsNov 17, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;T;T;T;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.81
.;.;T;.;T
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.35
T;T;T;T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.4
M;M;.;M;M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.92
N;N;N;N;N
REVEL
Uncertain
0.33
Sift
Benign
0.28
T;T;T;T;T
Sift4G
Benign
0.14
T;T;D;T;T
Polyphen
0.78
P;P;.;P;P
Vest4
0.44
MutPred
0.45
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
0.91
MPC
1.7
ClinPred
0.95
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.63
gMVP
0.48

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: rs1941540936; hg19: chr11-116706857; API