rs73885319

Positions:

chr22-36265860-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5BP4BA1

The ENST00000397278.8(APOL1):c.1024A>G(p.Ser342Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,072 control chromosomes in the GnomAD database, including 2,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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).

Frequency

Genomes: 𝑓 0.062 ( 1084 hom., cov: 31)

Exomes 𝑓: 0.0061 ( 1074 hom. )

Consequence

APOL1
ENST00000397278.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:7U:2O:2

Conservation

PhyloP100: 0.277

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP5

Variant 22-36265860-A-G is Pathogenic according to our data. Variant chr22-36265860-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 277678.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, risk_factor=2, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.01211217). . Strength limited to SUPPORTING due to the PP5.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOL1	NM_003661.4 linkuse as main transcript	c.1024A>G	p.Ser342Gly	missense_variant	6/6	ENST00000397278.8	NP_003652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOL1	ENST00000397278.8 linkuse as main transcript	c.1024A>G	p.Ser342Gly	missense_variant	6/6	1	NM_003661.4	ENSP00000380448	A2	O14791-1

Frequencies

GnomAD3 genomes

AF:

0.0624

AC:

9495

AN:

152060

Hom.:

1084

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

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:

0.000206

Gnomad OTH

AF:

0.0340

GnomAD3 exomes

AF:

0.0161

AC:

4039

AN:

251414

Hom.:

478

AF XY:

0.0116

AC XY:

1574

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.00671

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00609

AC:

8910

AN:

1461894

Hom.:

1074

Cov.:

AF XY:

0.00524

AC XY:

3810

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.237

Gnomad4 AMR exome

AF:

0.00729

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00950

GnomAD4 genome

AF:

0.0624

AC:

9496

AN:

152178

Hom.:

1084

Cov.:

AF XY:

0.0593

AC XY:

4410

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.222

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0138

Hom.:

370

Bravo

AF:

0.0705

ESP6500AA

AF:

0.226

AC:

994

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0206

AC:

2496

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:7Uncertain:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

risk factor, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	This variant is associated with the following publications: (PMID: 28696248, 27650483, 32581362, 21910715, 24379297, 23768513, 24518129, 25993319, 22832513, 24206458, 20635188, 20647424, 30173819, 30315176) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 342 of the APOL1 protein (p.Ser342Gly). This variant is present in population databases (rs73885319, gnomAD 23%), and has an allele count higher than expected for a pathogenic variant. This variant, along with c.1152T>G (p.Ile384Met), constitutes the ‚ÄúG1‚Äù allele of APOL1. This allele is associated with increased risk for several forms of kidney disease in individuals of African-American ancestry when present in homozygosity or in trans with the ‚ÄúG2‚Äù allele (c.1164_1169delTTATAA (p.Asn388_Tyr389del)). Several large case-control studies have shown a 6- to 47-fold increased risk of focal segmental glomerulosclerosis, HIV-associated nephropathy, or non-diabetic end-stage kidney disease in individuals with homozygous G1, homozygous G2, or G1 in trans with G2 alleles (PMID: 20647424, 20635188, 21997394). Similar studies in African populations have generally recapitulated these findings, but these studies are based on a relatively small number of individuals (PMID: 30340464, 25788523). A recent PheWAS study also appears to support these findings, although the risk of end-stage kidney disease may be smaller than initially assumed (closer to 3- to 4-fold; PMID: 32247630). p.Ile384Met and p.Ser342Gly are almost always present on the same allele (in cis), but p.Ser342Gly is thought to be the main driver of increased risk (PMID: 21997394). p.Ile384Met is therefore classified as Benign at Invitae. ClinVar contains an entry for this variant (Variation ID: 277678). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects APOL1 function (PMID: 30332315, 32675303). In summary, this variant has been shown to confer an increased risk for kidney disease, either in homozygosity or in trans with the G2 allele. However, its significance when present in heterozygosity is unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance. -

Nephrotic range proteinuria

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

not specified

Pathogenic:1

Likely risk allele, criteria provided, single submitter

clinical testing

Mendelics

Feb 15, 2023

- -

Glomerulonephritis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Focal segmental glomerulosclerosis;C2237347:Sickled erythrocytes

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Proteinuria

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Focal segmental glomerulosclerosis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Focal segmental glomerulosclerosis;C0403397:Steroid-resistant nephrotic syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

APOL1-associated kidney disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 29, 2023

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). -

Hyalinosis, Segmental Glomerular

Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

See compound het c.[1024A>G;1152T>G] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.11

DANN

Benign

0.092

DEOGEN2

Benign

0.026

T;T;.;.;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00018

LIST_S2

Benign

0.59

.;.;T;T;T

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.7

N;N;.;.;N

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

4.5

N;N;N;N;N

REVEL

Benign

0.081

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;.;B;B

Vest4

0.031

MPC

0.056

ClinPred

0.0012

GERP RS

-0.38

Varity_R

0.016

gMVP

0.20

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