rs121912726

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

Scores

3
10
6

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.22
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 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
APOA1NM_000039.3 linkuse as main transcriptc.220T>C p.Trp74Arg missense_variant 4/4 ENST00000236850.5 NP_000030.1
APOA1-ASNR_126362.1 linkuse as main transcriptn.123+153A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APOA1ENST00000236850.5 linkuse as main transcriptc.220T>C p.Trp74Arg missense_variant 4/41 NM_000039.3 ENSP00000236850 P1
APOA1-ASENST00000669664.1 linkuse as main transcriptn.74+153A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
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 providedliterature onlyOMIMJun 15, 1996- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 25, 2023For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;T;T;T;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.68
.;.;T;.;T
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Uncertain
2.7
M;M;.;M;M
MutationTaster
Benign
9.4e-9
A;A;A;A;A
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-4.1
D;D;D;D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.016
D;D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;D;D
Polyphen
0.97
D;D;.;D;D
Vest4
0.78
MutPred
0.78
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
0.88
MPC
2.1
ClinPred
0.97
D
GERP RS
2.6
Varity_R
0.93
gMVP
0.66

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: rs121912726; hg19: chr11-116707108; API