Genetic Variant APOL3:p.Val161Met (chr22-36141715-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_145639.2(APOL3):c.481G>A(p.Val161Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0537 in 1,613,978 control chromosomes in the GnomAD database, including 2,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.046 ( 215 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2506 hom. )

Consequence

APOL3
NM_145639.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.101

Publications

13 publications found

Variant links:

Genes affected

APOL3 (HGNC:14868): (apolipoprotein L3) This gene is a member of the apolipoprotein L gene family, and it is present in a cluster with other family members on chromosome 22. The encoded protein is found in the cytoplasm, where it may affect the movement of lipids, including cholesterol, and/or allow the binding of lipids to organelles. In addition, expression of this gene is up-regulated by tumor necrosis factor-alpha in endothelial cells lining the normal and atherosclerotic iliac artery and aorta. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

APOL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005245805).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOL3	NM_145639.2 link	c.481G>A	p.Val161Met	missense_variant	Exon 4 of 4	ENST00000424878.4	NP_663614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOL3	ENST00000424878.4 link	c.481G>A	p.Val161Met	missense_variant	Exon 4 of 4	1	NM_145639.2	ENSP00000415779.3

Frequencies

GnomAD3 genomes

AF:

0.0463

AC:

7053

AN:

152192

Hom.:

215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0666

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0847

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0634

Gnomad OTH

AF:

0.0630

GnomAD2 exomes

AF:

0.0438

AC:

10958

AN:

250398

AF XY:

0.0449

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0399

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0776

Gnomad NFE exome

AF:

0.0595

Gnomad OTH exome

AF:

0.0576

GnomAD4 exome

AF:

0.0544

AC:

79554

AN:

1461668

Hom.:

2506

Cov.:

AF XY:

0.0535

AC XY:

38923

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0107

AC:

359

AN:

33480

American (AMR)

AF:

0.0413

AC:

1849

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0284

AC:

743

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0132

AC:

1141

AN:

86248

European-Finnish (FIN)

AF:

0.0753

AC:

4011

AN:

53272

Middle Eastern (MID)

AF:

0.0636

AC:

367

AN:

5768

European-Non Finnish (NFE)

AF:

0.0610

AC:

67800

AN:

1111964

Other (OTH)

AF:

0.0544

AC:

3283

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

4892

9785

14677

19570

24462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2412

4824

7236

9648

12060

<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:

0.0463

AC:

7046

AN:

152310

Hom.:

215

Cov.:

AF XY:

0.0465

AC XY:

3463

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0124

AC:

516

AN:

41572

American (AMR)

AF:

0.0663

AC:

1015

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00994

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0847

AC:

898

AN:

10606

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0634

AC:

4315

AN:

68030

Other (OTH)

AF:

0.0619

AC:

131

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

353

706

1059

1412

1765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0531

Hom.:

554

Bravo

AF:

0.0432

TwinsUK

AF:

0.0639

AC:

237

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.0631

AC:

543

ExAC

AF:

0.0414

AC:

5030

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0660

EpiControl

AF:

0.0651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.1

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.060

T;.;.;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.78

T;T;.;.;T

MetaRNN

Benign

0.0052

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;.;.;.

PhyloP100

-0.10

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.0

N;.;D;D;.

REVEL

Benign

0.094

Sift

Uncertain

0.029

D;.;D;D;.

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

0.93

P;.;.;.;P

Vest4

0.18

MPC

0.50

ClinPred

0.045

GERP RS

-1.5

Varity_R

0.086

gMVP

0.56

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over