rs73885319

Variant names:

• chr22-36265860-A-G
• rs73885319
• NM_003661.4:c.1024A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_003661.4(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. 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. S342T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (1084 hom., cov: 31)
  • Exomes 𝑓: 0.0061 (1074 hom.)
• Consequence: APOL1 NM_003661.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:9 U:2 O:2
• Conservation: PhyloP100: 0.277
• Publications: 339 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 -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 VariationId is 277678.
• 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.

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.1024A>G	p.Ser342Gly	missense	Exon 6 of 6	NP_003652.2
	APOL1	NM_145343.3		c.1072A>G	p.Ser358Gly	missense	Exon 7 of 7	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.1024A>G	p.Ser342Gly	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.1024A>G	p.Ser342Gly	missense	Exon 6 of 6	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.1072A>G	p.Ser358Gly	missense	Exon 7 of 7	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.1111A>G	p.Ser371Gly	missense	Exon 7 of 7	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9495 AN: 152060 Hom.: 1084 Cov.: 31

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

GnomAD2 exomes AF: 0.0161 AC: 4039 AN: 251414 AF XY: 0.0116

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 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.: 36 AF XY: 0.00524 AC XY: 3810 AN XY: 727248

African (AFR) AF: 0.237 AC: 7933 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112012

Other (OTH) AF: 0.00950 AC: 574 AN: 60396

GnomAD4 genome AF: 0.0624 AC: 9496 AN: 152178 Hom.: 1084 Cov.: 31 AF XY: 0.0593 AC XY: 4410 AN XY: 74422

African (AFR) AF: 0.222 AC: 9209 AN: 41460

American (AMR) AF: 0.0131 AC: 201 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0207 Hom.: 1190

Bravo AF: 0.0705

ESP6500AA AF: 0.226 AC: 994

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0206 AC: 2496

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Focal segmental glomerulosclerosis 4, susceptibility to (2)
-	1	-	APOL1-associated kidney disease (1)
1	-	-	Focal segmental glomerulosclerosis (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 provided (2)
1	-	-	Proteinuria (1)
-	-	-	Hyalinosis, Segmental Glomerular (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.11
DANN	Benign	0.092
DEOGEN2	Benign	0.026	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00018	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.28
PrimateAI	Benign	0.25	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.056
ClinPred		0.0012	T
GERP RS		-0.38
Varity_R		0.016
gMVP		0.20
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: rs73885319; hg19: chr22-36661906; COSMIC: COSV59869297; COSMIC: COSV59869297;