22-36265988-T-G

Position:

chr22-36265988-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 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 ( 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:6U:1B:4O:1

Conservation

PhyloP100: -0.623

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 -13 ACMG points.

BP4

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

BP6

Variant 22-36265988-T-G is Benign according to our data. Variant chr22-36265988-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 127198.We mark this variant Likely_benign, oryginal submissions are: {risk_factor=1, Benign=4, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 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.1152T>G	p.Ile384Met	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.1152T>G	p.Ile384Met	missense_variant	6/6	1	NM_003661.4	ENSP00000380448	A2	O14791-1

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

GnomAD3 exomes

AF:

0.0155

AC:

3879

AN:

249548

Hom.:

458

AF XY:

0.0114

AC XY:

1540

AN XY:

135202

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 SAS exome

AF:

0.0000985

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

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.00697

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00924

GnomAD4 genome

AF:

0.0618

AC:

9330

AN:

151050

Hom.:

1060

Cov.:

AF XY:

0.0587

AC XY:

4337

AN XY:

73862

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.0130

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0334

Alfa

AF:

0.00994

Hom.:

263

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:6Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephrotic range proteinuria

Pathogenic:1