Variant rs71785313 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4BA1

The ENST00000397278.8(APOL1):c.1164_1169del(p.Asn388_Tyr389del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,612,914 control chromosomes in the GnomAD database, including 748 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

Frequency

Genomes: 𝑓 0.039 ( 410 hom., cov: 31)

Exomes 𝑓: 0.0037 ( 338 hom. )

Consequence

APOL1
ENST00000397278.8 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:3U:1B:2O:3

Conservation

PhyloP100: -0.259

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 Likely_benign. Variant got -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000397278.8.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 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.1164_1169del	p.Asn388_Tyr389del	inframe_deletion	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.1164_1169del	p.Asn388_Tyr389del	inframe_deletion	6/6	1	NM_003661.4	ENSP00000380448	A2	O14791-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5899

AN:

152120

Hom.:

410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.00976

AC:

2429

AN:

248746

Hom.:

144

AF XY:

0.00713

AC XY:

961

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.00569

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000978

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00369

AC:

5397

AN:

1460676

Hom.:

338

AF XY:

0.00303

AC XY:

2204

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00782

GnomAD4 genome

AF:

0.0388

AC:

5908

AN:

152238

Hom.:

410

Cov.:

AF XY:

0.0378

AC XY:

2815

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0196

Hom.:

Bravo

AF:

0.0451

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:3Uncertain:1Benign:2Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 4, susceptibility to

Pathogenic:1Other:2

risk factor, no assertion criteria provided	literature only	OMIM	Aug 13, 2010	- -
risk factor, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Feb 27, 2015	G2 -
Likely risk allele, criteria provided, single submitter	clinical testing	Mendelics	Mar 24, 2023	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This variant, c.1164_1169del, results in the deletion of 2 amino acid(s) of the APOL1 protein (p.Asn388_Tyr389del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs143830837, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This variant constitutes the ‚ÄúG2‚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 ‚ÄúG1‚Äù allele (which is composed of the c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met) variants in cis). 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). ClinVar contains an entry for this variant (Variation ID: 6081). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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 G1 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

- -

Focal segmental glomerulosclerosis

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 29, 2024

- -

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

APOL1 c.1164_1169del (p.Asn388_Tyr389del), traditionally referred to as G1, has been associated with increased risk for multiple renal diseases in African Americans, particularly focal segmental glomerulosclerosis (FSGS), as well as an increased risk for end-stage kidney disease (ESKD). This variant is common in individuals of African ancestry (14%, Genome Aggregation Database (gnomAD); rs71785313) and is present in ClinVar (ID: 6081). Several small case-control studies have reported odds ratios between 3.92-25.1 for developing FSGS/HIVAN in homozygous individuals (OR=3.92 [95% CI 1.47-9.39] for FSGS/HIVAN Ito 2014, OR=14.4 [95% CI 1.7-116.3] for HIVAN, OR=25.1 [95% CI 8.8-83.3] for FSGS Kopp 2011, OR=5.69 [95% CI not given, P<0.00001] Limou 2015). In vitro and in vivo studies provide some evidence that these alleles impact protein function (Beckerman 2017, Hayek 2017). In summary, this variant is an established risk factor for chronic kidney disease in homozygous state. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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