Genetic Variant APOA5:p.Gln139Lys (chr11-116790814-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001371904.1(APOA5):c.415C>A(p.Gln139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.70

Publications

0 publications found

Variant links:

Genes affected

APOA5 (HGNC:17288): (apolipoprotein A5) The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

APOA5 Gene-Disease associations (from GenCC):

hypertriglyceridemia 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
hyperlipoproteinemia type V
Inheritance: AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

APOA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA5	NM_001371904.1 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 3 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 4 of 4		NP_001160070.1	Q6Q788A0A0B4RUS7
APOA5	NM_052968.5 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 4 of 4		NP_443200.2	Q6Q788A0A0B4RUS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOA5	ENST00000227665.9 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 3 of 3	1	NM_001371904.1	ENSP00000227665.4	Q6Q788
APOA5	ENST00000433069.2 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 4 of 4	1		ENSP00000399701.2	Q6Q788
APOA5	ENST00000673688.1 link	c.499C>A	p.Gln167Lys	missense_variant	Exon 3 of 3			ENSP00000501141.1	A0A669KB69
APOA5	ENST00000542499.5 link	c.415C>A	p.Gln139Lys	missense_variant	Exon 4 of 4	5		ENSP00000445002.1	Q6Q788

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.75

.;T;T

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

2.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.027

D;D;D

Sift4G

Benign

0.097

T;T;T

Polyphen

0.96

D;D;.

Vest4

0.22

MutPred

0.73

Gain of ubiquitination at Q139 (P = 0.0117);Gain of ubiquitination at Q139 (P = 0.0117);Gain of ubiquitination at Q139 (P = 0.0117);

MVP

0.92

MPC

1.3

ClinPred

0.97

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.86

Mutation Taster

=90/10

polymorphism

(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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chr11-116790814-G-T

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