11-116837121-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000039.3(APOA1):c.80C>T(p.Pro27Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,224 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

APOA1
NM_000039.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-116837121-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17914.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000039.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOA1	NM_000039.3	MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 3 of 4	NP_000030.1	A0A024R3E3
APOA1	NM_001318017.2		c.80C>T	p.Pro27Leu	missense	Exon 3 of 4	NP_001304946.1	A0A024R3E3
APOA1	NM_001318018.2		c.80C>T	p.Pro27Leu	missense	Exon 3 of 4	NP_001304947.1	P02647

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOA1	ENST00000236850.5	TSL:1 MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 3 of 4	ENSP00000236850.3	P02647
APOA1	ENST00000375323.5	TSL:1	c.80C>T	p.Pro27Leu	missense	Exon 2 of 3	ENSP00000364472.1	P02647
APOA1	ENST00000855312.1		c.80C>T	p.Pro27Leu	missense	Exon 3 of 4	ENSP00000525371.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.8

PhyloP100

6.2

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.68

MutPred

0.31

Loss of disorder (P = 0.0315)

MVP

0.93

MPC

1.5

ClinPred

0.95

GERP RS

4.8

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.26

Mutation Taster

=26/74

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over