11-116835821-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000039.3(APOA1):ā€‹c.791T>Cā€‹(p.Leu264Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

APOA1
NM_000039.3 missense

Scores

4
13
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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 linkc.791T>C p.Leu264Pro 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 linkc.791T>C p.Leu264Pro missense_variant 4/41 NM_000039.3 ENSP00000236850.3 P02647

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460730
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726684
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 11, 2024The p.L264P variant (also known as c.791T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 791. The leucine at codon 264 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious 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
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;T;T;T;T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.48
.;.;T;.;T
M_CAP
Pathogenic
0.44
D
MetaRNN
Uncertain
0.74
D;D;D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.8
M;M;.;M;M
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-4.1
D;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;D;.;D;D
Vest4
0.62
MutPred
0.47
Gain of disorder (P = 0.0336);Gain of disorder (P = 0.0336);.;Gain of disorder (P = 0.0336);Gain of disorder (P = 0.0336);
MVP
0.96
MPC
2.0
ClinPred
0.94
D
GERP RS
4.6
Varity_R
0.86
gMVP
0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-116706537; API