rs60910145

Variant names:

• chr22-36265988-T-G
• rs60910145
• NM_003661.4:c.1152T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-36265988-T-G
• chr22-36265988-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:7 U:1 B:4 O:1
• Conservation: PhyloP100: -0.623
• Publications: 264 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 -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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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	O14791-2
	APOL1	NM_001136540.2		c.1152T>G	p.Ile384Met	missense	Exon 6 of 6	NP_001130012.1	O14791-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL1	ENST00000397278.8	TSL:1 MANE Select	c.1152T>G	p.Ile384Met	missense	Exon 6 of 6	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.1200T>G	p.Ile400Met	missense	Exon 7 of 7	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.1239T>G	p.Ile413Met	missense	Exon 7 of 7	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9330 AN: 150930 Hom.: 1060 Cov.: 32

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

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.: 36 AF XY: 0.00511 AC XY: 3717 AN XY: 726936

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: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111758

Other (OTH) AF: 0.00924 AC: 558 AN: 60358

GnomAD4 genome AF: 0.0618 AC: 9330 AN: 151050 Hom.: 1060 Cov.: 32 AF XY: 0.0587 AC XY: 4337 AN XY: 73862

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: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67982

Other (OTH) AF: 0.0334 AC: 70 AN: 2096

Alfa AF: 0.0182 Hom.: 526

Bravo AF: 0.0690

ESP6500AA AF: 0.222 AC: 979

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0200 AC: 2432

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	APOL1-associated kidney disease (1)
1	-	-	Focal segmental glomerulosclerosis (1)
1	-	-	Focal segmental glomerulosclerosis 4, susceptibility to (1)
1	-	-	Focal segmental glomerulosclerosis;C0403397:Steroid-resistant nephrotic syndrome (1)
1	-	-	Focal segmental glomerulosclerosis;C2237347:Sickled erythrocytes (1)
1	-	-	Glomerulonephritis (1)
1	-	-	Nephrotic range proteinuria (1)
-	-	1	not specified (1)
1	-	-	Proteinuria (1)
-	-	-	Hyalinosis, Segmental Glomerular (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.2
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00062	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.62
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.029
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.63	P
Vest4		0.044
MPC		0.090
ClinPred		0.0023	T
GERP RS		0.33
Varity_R		0.031
gMVP		0.062
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs60910145; hg19: chr22-36662034; COSMIC: COSV59869303; COSMIC: COSV59869303;