chr11-116835888-G-T

Variant names:

Variant summary

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

The NM_000039.3(APOA1):c.724C>A(p.Leu242Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L242L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

APOA1
NM_000039.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.61

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3 link	c.724C>A	p.Leu242Met	missense_variant	Exon 4 of 4	ENST00000236850.5	NP_000030.1	P02647A0A024R3E3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5 link	c.724C>A	p.Leu242Met	missense_variant	Exon 4 of 4	1	NM_000039.3	ENSP00000236850.3		P02647

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249946

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000188

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460906

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26132

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.0000191

AC:

AN:

52474

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111992

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60386

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000394

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000121

AC:

0.000120534

AN:

0.000120534

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000478

AC:

0.000477555

AN:

0.000477555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 242 of the APOA1 protein (p.Leu242Met). This variant is present in population databases (rs368503162, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with APOA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1757901). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Nov 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L242M variant (also known as c.724C>A), located in coding exon 3 of the APOA1 gene, results from a C to A substitution at nucleotide position 724. The leucine at codon 242 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T;T;T;T

Eigen

Benign

0.18

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.73

.;.;T;.;T

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.9

M;M;.;M;M

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

D;D;T;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.55

MVP

0.90

MPC

1.6

ClinPred

0.83

GERP RS

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.58

gMVP

0.49

Mutation Taster

=84/16

polymorphism

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over