Genetic Variant APOL3:p.Ala157Thr (chr22-36141727-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145639.2(APOL3):c.469G>A(p.Ala157Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,056 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 89 hom. )

Consequence

APOL3
NM_145639.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.05

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064413548).

BP6

Variant 22-36141727-C-T is Benign according to our data. Variant chr22-36141727-C-T is described in ClinVar as Benign. ClinVar VariationId is 774970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00323 (492/152358) while in subpopulation SAS AF = 0.0284 (137/4824). AF 95% confidence interval is 0.0245. There are 5 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145639.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL3	NM_145639.2	MANE Select	c.469G>A	p.Ala157Thr	missense	Exon 4 of 4	NP_663614.1	O95236-2
APOL3	NM_145640.2		c.682G>A	p.Ala228Thr	missense	Exon 3 of 3	NP_663615.1	O95236-1
APOL3	NM_001393587.1		c.472G>A	p.Ala158Thr	missense	Exon 5 of 5	NP_001380516.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL3	ENST00000424878.4	TSL:1 MANE Select	c.469G>A	p.Ala157Thr	missense	Exon 4 of 4	ENSP00000415779.3	O95236-2
APOL3	ENST00000349314.7	TSL:1	c.682G>A	p.Ala228Thr	missense	Exon 3 of 3	ENSP00000344577.2	O95236-1
APOL3	ENST00000361710.6	TSL:1	c.82G>A	p.Ala28Thr	missense	Exon 4 of 4	ENSP00000355164.2	O95236-3

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

492

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00314

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00661

AC:

1654

AN:

250386

AF XY:

0.00828

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00589

GnomAD4 exome

AF:

0.00451

AC:

6592

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

3967

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.00324

AC:

145

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

368

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0304

AC:

2620

AN:

86250

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.0213

AC:

123

AN:

5768

European-Non Finnish (NFE)

AF:

0.00262

AC:

2917

AN:

1111958

Other (OTH)

AF:

0.00629

AC:

380

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

443

886

1330

1773

2216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00323

AC:

492

AN:

152358

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41582

American (AMR)

AF:

0.00359

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

68042

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00381

Hom.:

Bravo

AF:

0.00265

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00693

AC:

841

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00558

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.0090

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.56

PhyloP100

-1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.0

REVEL

Benign

0.074

Sift

Benign

0.17

Sift4G

Benign

0.42

Polyphen

0.79

Vest4

0.096

MVP

0.13

MPC

0.17

ClinPred

0.0034

GERP RS

-0.31

Varity_R

0.051

gMVP

0.28

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over