22-36265284-G-A

Variant names:

• chr22-36265284-G-A
• rs2239785
• NM_003661.4:c.448G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003661.4(APOL1):​c.448G>A​(p.Glu150Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,690 control chromosomes in the GnomAD database, including 510,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38824 hom., cov: 31)
  • Exomes 𝑓: 0.80 (471605 hom.)
• Consequence: APOL1 NM_003661.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.258
• Publications: 81 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4776589E-6).
• BP6: Variant 22-36265284-G-A is Benign according to our data. Variant chr22-36265284-G-A is described in ClinVar as Benign. ClinVar VariationId is 1168875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.804 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL1	NM_003661.4	MANE Select	c.448G>A	p.Glu150Lys	missense	Exon 6 of 6	NP_003652.2
	APOL1	NM_145343.3		c.496G>A	p.Glu166Lys	missense	Exon 7 of 7	NP_663318.1
	APOL1	NM_001136540.2		c.448G>A	p.Glu150Lys	missense	Exon 6 of 6	NP_001130012.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL1	ENST00000397278.8	TSL:1 MANE Select	c.448G>A	p.Glu150Lys	missense	Exon 6 of 6	ENSP00000380448.4
	APOL1	ENST00000319136.8	TSL:1	c.496G>A	p.Glu166Lys	missense	Exon 7 of 7	ENSP00000317674.4
	APOL1	ENST00000438034.6	TSL:4	c.535G>A	p.Glu179Lys	missense	Exon 7 of 7	ENSP00000404525.2

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104059 AN: 151950 Hom.: 38808 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.721

GnomAD2 exomes AF: 0.791 AC: 198800 AN: 251180 AF XY: 0.797

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.818

Gnomad EAS exome AF: 0.834

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.805

GnomAD4 exome AF: 0.800 AC: 1168760 AN: 1461622 Hom.: 471605 Cov.: 76 AF XY: 0.800 AC XY: 582048 AN XY: 727150

African (AFR) AF: 0.348 AC: 11626 AN: 33438

American (AMR) AF: 0.874 AC: 39031 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 21442 AN: 26122

East Asian (EAS) AF: 0.833 AC: 33062 AN: 39700

South Asian (SAS) AF: 0.816 AC: 70347 AN: 86236

European-Finnish (FIN) AF: 0.842 AC: 45006 AN: 53420

Middle Eastern (MID) AF: 0.729 AC: 4203 AN: 5768

European-Non Finnish (NFE) AF: 0.807 AC: 896844 AN: 1111920

Other (OTH) AF: 0.782 AC: 47199 AN: 60366

GnomAD4 genome AF: 0.685 AC: 104116 AN: 152068 Hom.: 38824 Cov.: 31 AF XY: 0.694 AC XY: 51587 AN XY: 74340

African (AFR) AF: 0.360 AC: 14933 AN: 41432

American (AMR) AF: 0.816 AC: 12481 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 2818 AN: 3470

East Asian (EAS) AF: 0.824 AC: 4261 AN: 5170

South Asian (SAS) AF: 0.823 AC: 3963 AN: 4814

European-Finnish (FIN) AF: 0.842 AC: 8917 AN: 10586

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54296 AN: 67988

Other (OTH) AF: 0.723 AC: 1527 AN: 2112

Alfa AF: 0.765 Hom.: 176916

Bravo AF: 0.669

TwinsUK AF: 0.811 AC: 3006

ALSPAC AF: 0.807 AC: 3109

ESP6500AA AF: 0.374 AC: 1647

ESP6500EA AF: 0.796 AC: 6844

ExAC AF: 0.780 AC: 94686

Asia WGS AF: 0.811 AC: 2817 AN: 3478

EpiCase AF: 0.785

EpiControl AF: 0.791

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19239905, 22239288)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.26
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.031
Sift	Benign	0.43	T
Sift4G	Benign	0.39	T
Polyphen		0.99	D
Vest4		0.10
MPC		0.35
ClinPred		0.028	T
GERP RS		-2.2
Varity_R		0.035
gMVP		0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2239785; hg19: chr22-36661330; COSMIC: COSV59868177; COSMIC: COSV59868177;