22-36265988-T-G

Variant names:

Variant summary

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

The NM_003661.4(APOL1):c.1152T>G(p.Ile384Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,612,334 control chromosomes in the GnomAD database, including 2,103 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 Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I384F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 1060 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 1043 hom. )

Consequence

APOL1
NM_003661.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:7U:1B:4O:1

Conservation

PhyloP100: -0.623

Publications

264 publications found

Variant links:

Genes affected

APOL1 (HGNC:618): (apolipoprotein L1) This gene encodes a secreted high density lipoprotein which binds to apolipoprotein A-I. Apolipoprotein A-I is a relatively abundant plasma protein and is the major apoprotein of HDL. It is involved in the formation of most cholesteryl esters in plasma and also promotes efflux of cholesterol from cells. This apolipoprotein L family member may play a role in lipid exchange and transport throughout the body, as well as in reverse cholesterol transport from peripheral cells to the liver. Several different transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

APOL1 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 4, susceptibility to
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

APOL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.008493423).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003661.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOL1	NM_003661.4	MANE Select	c.1152T>G	p.Ile384Met	missense	Exon 6 of 6	NP_003652.2
APOL1	NM_145343.3		c.1200T>G	p.Ile400Met	missense	Exon 7 of 7	NP_663318.1
APOL1	NM_001136540.2		c.1152T>G	p.Ile384Met	missense	Exon 6 of 6	NP_001130012.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOL1	ENST00000397278.8	TSL:1 MANE Select	c.1152T>G	p.Ile384Met	missense	Exon 6 of 6	ENSP00000380448.4
APOL1	ENST00000319136.8	TSL:1	c.1200T>G	p.Ile400Met	missense	Exon 7 of 7	ENSP00000317674.4
APOL1	ENST00000438034.6	TSL:4	c.1239T>G	p.Ile413Met	missense	Exon 7 of 7	ENSP00000404525.2

Frequencies

GnomAD3 genomes

AF:

0.0618

AC:

9330

AN:

150930

Hom.:

1060

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0338

GnomAD2 exomes

AF:

0.0155

AC:

3879

AN:

249548

AF XY:

0.0114

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.00644

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

AF:

0.00595

AC:

8699

AN:

1461284

Hom.:

1043

Cov.:

AF XY:

0.00511

AC XY:

3717

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.232

AC:

7758

AN:

33436

American (AMR)

AF:

0.00697

AC:

311

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000163

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111758

Other (OTH)

AF:

0.00924

AC:

558

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

348

696

1045

1393

1741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.0618

AC:

9330

AN:

151050

Hom.:

1060

Cov.:

AF XY:

0.0587

AC XY:

4337

AN XY:

73862

show subpopulations

African (AFR)

AF:

0.224

AC:

9047

AN:

40462

American (AMR)

AF:

0.0130

AC:

199

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67982

Other (OTH)

AF:

0.0334

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

359

718

1077

1436

1795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0182

Hom.:

526

Bravo

AF:

0.0690

ESP6500AA

AF:

0.222

AC:

979

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0200

AC:

2432

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:7Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The G1 allele comprises two single nucleotide polymorphisms (c.[1024A>G;1152T>G], p.[Ser342Gly;Ile384Met]), however, the risk associated with the G1 allele is considered to be due to only the c.1024A>G, p.Ser342Gly variant (Kopp et al., 2011). The other polymorphism (c.1152T>G, p.Ile384Met) associated with the G1 allele does not confer an increased risk in isolation (Kruzel-Davila et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32581362, 27650483, 30173819, 28696248, 20647424, 20635188, 24206458, 22832513, 25993319, 24518129, 23768513, 24379297)

Nephrotic range proteinuria

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Focal segmental glomerulosclerosis 4, susceptibility to

Pathogenic:1

Sep 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Glomerulonephritis

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Focal segmental glomerulosclerosis;C2237347:Sickled erythrocytes

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Proteinuria

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Focal segmental glomerulosclerosis

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Focal segmental glomerulosclerosis;C0403397:Steroid-resistant nephrotic syndrome

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

APOL1-associated kidney disease

Uncertain:1

Aug 29, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sequence analysis identified the presence of a single APOL1 risk allele in a heterozygous state (G1). The G1 allele is composed of two missense variants: G1G (p.S342G) and G1M (p.I384M). APOL1 risk alleles occur at high frequency among populations of African ancestry (22-24% and 13-14% for G1 and G2, respectively) and are absent or nearly absent from other populations. Inheriting two risk variants greatly increases risk of kidney disease, whereas inheriting one risk allele confers minimal or no risk (Friedman DJ et al., PMID: 32616495). APOL1-associated kidney disease includes focal segmental glomerulosclerosis, CKD associated with hypertension, HIV, systemic lupus erythematosus (SLE), and sickle cell disease, among others (Friedman DJ et al., PMID: 32616495).

not specified

Benign:1

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hyalinosis, Segmental Glomerular

Other:1

Mar 04, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:risk factor

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See compound allele p.[Ser342Gly; Ile384Met]

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.2

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.017

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00062

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

-0.62

PrimateAI

Benign

0.38

PROVEAN

Benign

0.19

REVEL

Benign

0.029

Sift

Benign

0.14

Sift4G

Benign

0.12

Polyphen

0.63

Vest4

0.044

MPC

0.090

ClinPred

0.0023

GERP RS

0.33

Varity_R

0.031

gMVP

0.062

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over