rs71785313

Variant names:

• chr22-36265995-AATAATT-A
• rs71785313
• NM_003661.4:c.1164_1169delTTATAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4 BA1

The NM_003661.4(APOL1):​c.1164_1169delTTATAA​(p.Asn388_Tyr389del) variant causes a disruptive 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 NM_003661.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:4 U:1 B:2 O:3
• Conservation: PhyloP100: -0.259
• Publications: 225 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: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003661.4.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 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.1164_1169delTTATAA	p.Asn388_Tyr389del	disruptive_inframe_deletion	Exon 6 of 6	NP_003652.2
	APOL1	NM_145343.3		c.1212_1217delTTATAA	p.Asn404_Tyr405del	disruptive_inframe_deletion	Exon 7 of 7	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.1164_1169delTTATAA	p.Asn388_Tyr389del	disruptive_inframe_deletion	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.1164_1169delTTATAA	p.Asn388_Tyr389del	disruptive_inframe_deletion	Exon 6 of 6	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.1212_1217delTTATAA	p.Asn404_Tyr405del	disruptive_inframe_deletion	Exon 7 of 7	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.1251_1256delTTATAA	p.Asn417_Tyr418del	disruptive_inframe_deletion	Exon 7 of 7	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5899 AN: 152120 Hom.: 410 Cov.: 31

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

GnomAD2 exomes AF: 0.00976 AC: 2429 AN: 248746 AF XY: 0.00713

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 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

African (AFR) AF: 0.136 AC: 4551 AN: 33406

American (AMR) AF: 0.00655 AC: 292 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111444

Other (OTH) AF: 0.00782 AC: 472 AN: 60334

GnomAD4 genome AF: 0.0388 AC: 5908 AN: 152238 Hom.: 410 Cov.: 31 AF XY: 0.0378 AC XY: 2815 AN XY: 74452

African (AFR) AF: 0.135 AC: 5623 AN: 41506

American (AMR) AF: 0.0137 AC: 209 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0196 Hom.: 28

Bravo AF: 0.0451

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
1	-	-	Focal segmental glomerulosclerosis (1)
1	-	-	Focal segmental glomerulosclerosis 4, susceptibility to (4)
1	-	-	Nephrotic range proteinuria (1)
-	-	1	not specified (1)
-	-	-	Hyalinosis, Segmental Glomerular (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=196/4	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs71785313;

hg19: chr22-36662041;

COSMIC: COSV106451415;

COSMIC: COSV106451415;