11-116837020-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000039.3(APOA1):c.181G>A(p.Ala61Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,144 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000039.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.181G>A | p.Ala61Thr | missense_variant | 3/4 | ENST00000236850.5 | |
APOA1-AS | NR_126362.1 | n.123+781C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOA1 | ENST00000236850.5 | c.181G>A | p.Ala61Thr | missense_variant | 3/4 | 1 | NM_000039.3 | P1 | |
APOA1-AS | ENST00000669664.1 | n.74+781C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00134 AC: 204AN: 152212Hom.: 5 Cov.: 33
GnomAD3 exomes AF: 0.00296 AC: 744AN: 251256Hom.: 11 AF XY: 0.00272 AC XY: 369AN XY: 135898
GnomAD4 exome AF: 0.00134 AC: 1958AN: 1461814Hom.: 41 Cov.: 36 AF XY: 0.00133 AC XY: 964AN XY: 727204
GnomAD4 genome AF: 0.00135 AC: 206AN: 152330Hom.: 5 Cov.: 33 AF XY: 0.00145 AC XY: 108AN XY: 74488
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 29, 2018 | Variant summary: APOA1 c.181G>A (p.Ala61Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 277088 control chromosomes, predominantly at a frequency of 0.04 within the East Asian subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4000 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA1 causing Apoliprotein A1 Amyloidosis phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.181G>A has been reported in the literature in individuals affected with Apoliprotein A1 deficiency, familial hypercholesterolemia, and Moyamoya disease (Matsunaga_1991, Pek_2017, Shoemaker_2015). These reports do not provide unequivocal conclusions about association of the variant with Apoliprotein A1 Amyloidosis, Apolipoprotein-A1 deficiency or familial hypercholestrolemia. Co-occurrences with other pathogenic variant(s) have been reported (APOA1 c.322C>T, p.Gln108X) in a female patient with apolipoprotein A-I deficiency, providing supporting evidence for a benign role (Matsunaga_1991). In addition, six control individuals who carry this variant showed normal plasma HDL cholesterol and apoA-I (Matsunaga_1991). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 19, 2021 | - - |
Familial visceral amyloidosis, Ostertag type Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Hypoalphalipoproteinemia, primary, 2, intermediate Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Hypoalphalipoproteinemia, primary, 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2020 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hypoalphalipoproteinemia, primary, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at