dbSNP rs5078: APOA1:p.Arg184Leu (chr11-116836061-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000039.3(APOA1):c.551G>T(p.Arg184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

APOA1
NM_000039.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

7 publications found

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 links:

APOA1-AS (HGNC:40079): (APOA1 antisense RNA)

APOA1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 18 uncertain in NM_000039.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3 link	c.551G>T	p.Arg184Leu	missense_variant	Exon 4 of 4	ENST00000236850.5	NP_000030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5 link	c.551G>T	p.Arg184Leu	missense_variant	Exon 4 of 4	1	NM_000039.3	ENSP00000236850.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000421

AC:

AN:

237620

AF XY:

0.00000768

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000931

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1452614

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722610

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46734

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110352

Other (OTH)

AF:

0.00

AC:

AN:

60152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0763859), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000831

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D;T;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

.;.;D;.;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.9

M;M;.;M;M

PhyloP100

2.3

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.5

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.66

MutPred

0.82

Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);.;Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);

MVP

0.95

MPC

1.8

ClinPred

0.97

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.73

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over