chr11-116835851-A-C

Variant summary

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

The NM_000039.3(APOA1):ā€‹c.761T>Gā€‹(p.Leu254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Synonymous variant affecting the same amino acid position (i.e. L254L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

APOA1
NM_000039.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0850
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 UniProt
APOA1NM_000039.3 linkuse as main transcriptc.761T>G p.Leu254Arg missense_variant 4/4 ENST00000236850.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOA1ENST00000236850.5 linkuse as main transcriptc.761T>G p.Leu254Arg missense_variant 4/41 NM_000039.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249214
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135482
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:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460794
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726714
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2023In 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. This variant is present in population databases (rs775381241, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 254 of the APOA1 protein (p.Leu254Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.049
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
T;T;T;T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.090
N
LIST_S2
Benign
0.62
.;.;T;.;T
M_CAP
Benign
0.058
D
MetaRNN
Uncertain
0.46
T;T;T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Uncertain
2.5
M;M;.;M;M
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.3
N;N;N;N;N
REVEL
Uncertain
0.33
Sift
Uncertain
0.010
D;D;D;D;D
Sift4G
Uncertain
0.021
D;D;D;D;D
Polyphen
0.90
P;P;.;P;P
Vest4
0.57
MutPred
0.41
Gain of methylation at L254 (P = 0.0216);Gain of methylation at L254 (P = 0.0216);.;Gain of methylation at L254 (P = 0.0216);Gain of methylation at L254 (P = 0.0216);
MVP
0.87
MPC
1.7
ClinPred
0.79
D
GERP RS
-3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.38
gMVP
0.59

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: rs775381241; hg19: chr11-116706567; API