rs121912726
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The ENST00000236850.5(APOA1):c.220T>C(p.Trp74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
APOA1
ENST00000236850.5 missense
ENST00000236850.5 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 3.22
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 Pathogenic. Variant got 10 ACMG points.
PM1
In a repeat 1 (size 21) in uniprot entity APOA1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000236850.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
Variant 11-116836392-A-G is Pathogenic according to our data. Variant chr11-116836392-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17928.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.220T>C | p.Trp74Arg | missense_variant | 4/4 | ENST00000236850.5 | NP_000030.1 | |
APOA1-AS | NR_126362.1 | n.123+153A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOA1 | ENST00000236850.5 | c.220T>C | p.Trp74Arg | missense_variant | 4/4 | 1 | NM_000039.3 | ENSP00000236850 | P1 | |
APOA1-AS | ENST00000669664.1 | n.74+153A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial amyloid polyneuropathy, Iowa type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 15, 1996 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24702826). 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. ClinVar contains an entry for this variant (Variation ID: 17928). This variant is also known as p.Trp50Arg. This missense change has been observed in individuals with autosomal dominant systemic amyloidosis (PMID: 7493166, 26299174, 27240838, 28953655, 31870425). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 74 of the APOA1 protein (p.Trp74Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;.;T;.;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;.;D;D
Vest4
MutPred
Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);.;Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);
MVP
MPC
2.1
ClinPred
D
GERP RS
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