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

Genomes: 𝑓 0.0014 ( 5 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 41 hom. )

Consequence

APOA1
NM_000039.3 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.289
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0033324957).
BP6
Variant 11-116837020-C-T is Benign according to our data. Variant chr11-116837020-C-T is described in ClinVar as [Benign]. Clinvar id is 302507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-116837020-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00135 (206/152330) while in subpopulation EAS AF= 0.0378 (196/5186). AF 95% confidence interval is 0.0335. There are 5 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APOA1NM_000039.3 linkuse as main transcriptc.181G>A p.Ala61Thr missense_variant 3/4 ENST00000236850.5
APOA1-ASNR_126362.1 linkuse as main transcriptn.123+781C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOA1ENST00000236850.5 linkuse as main transcriptc.181G>A p.Ala61Thr missense_variant 3/41 NM_000039.3 P1
APOA1-ASENST00000669664.1 linkuse as main transcriptn.74+781C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00134
AC:
204
AN:
152212
Hom.:
5
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0373
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00296
AC:
744
AN:
251256
Hom.:
11
AF XY:
0.00272
AC XY:
369
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0392
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00134
AC:
1958
AN:
1461814
Hom.:
41
Cov.:
36
AF XY:
0.00133
AC XY:
964
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0445
Gnomad4 SAS exome
AF:
0.000267
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.00233
GnomAD4 genome
AF:
0.00135
AC:
206
AN:
152330
Hom.:
5
Cov.:
33
AF XY:
0.00145
AC XY:
108
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0378
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00148
Hom.:
5
Bravo
AF:
0.00150
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.00284
AC:
345
Asia WGS
AF:
0.0140
AC:
49
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 29, 2018Variant 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 19, 2021- -
Familial visceral amyloidosis, Ostertag type Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Hypoalphalipoproteinemia, primary, 2, intermediate Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -
Hypoalphalipoproteinemia, primary, 2 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2020This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
10
DANN
Benign
0.75
DEOGEN2
Benign
0.093
T;T;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.48
.;.;.;T
MetaRNN
Benign
0.0033
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.20
N;N;N;N
REVEL
Benign
0.042
Sift
Benign
0.67
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.021
B;B;B;B
Vest4
0.25
MVP
0.63
MPC
0.59
ClinPred
0.0023
T
GERP RS
-4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.090
gMVP
0.11

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: rs12718465; hg19: chr11-116707736; COSMIC: COSV105846985; COSMIC: COSV105846985; API