chr22-36253745-G-A

Variant names:

• chr22-36253745-G-A
• rs112278014
• NM_003661.4:c.-20+526G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003661.4(APOL1):​c.-20+526G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 579,490 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (23 hom.)
• Consequence: APOL1 NM_003661.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.691
• Publications: 1 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 (BayesDel_noAF=-0.89).
• BP6: Variant 22-36253745-G-A is Benign according to our data. Variant chr22-36253745-G-A is described in ClinVar as Benign. ClinVar VariationId is 1256906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.016 (2432/152284) while in subpopulation AFR AF = 0.0512 (2125/41540). AF 95% confidence interval is 0.0493. There are 59 homozygotes in GnomAd4. There are 1135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

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.-20+526G>A		intron	N/A	NP_003652.2
	APOL1	NM_145343.3		c.-125-93G>A		intron	N/A	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.-59+526G>A		intron	N/A	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.-20+526G>A		intron	N/A	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.-125-93G>A		intron	N/A	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.-125-93G>A		intron	N/A	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2423 AN: 152166 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.00366 AC: 1564 AN: 427206 Hom.: 23 AF XY: 0.00345 AC XY: 777 AN XY: 224996

African (AFR) AF: 0.0515 AC: 620 AN: 12028

American (AMR) AF: 0.00690 AC: 125 AN: 18108

Ashkenazi Jewish (ASJ) AF: 0.00813 AC: 104 AN: 12800

East Asian (EAS) AF: 0.00 AC: 0 AN: 30240

South Asian (SAS) AF: 0.000216 AC: 9 AN: 41642

European-Finnish (FIN) AF: 0.000306 AC: 9 AN: 29386

Middle Eastern (MID) AF: 0.0102 AC: 21 AN: 2066

European-Non Finnish (NFE) AF: 0.00174 AC: 447 AN: 256428

Other (OTH) AF: 0.00934 AC: 229 AN: 24508

GnomAD4 genome AF: 0.0160 AC: 2432 AN: 152284 Hom.: 59 Cov.: 32 AF XY: 0.0152 AC XY: 1135 AN XY: 74470

African (AFR) AF: 0.0512 AC: 2125 AN: 41540

American (AMR) AF: 0.00850 AC: 130 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68028

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00398 Hom.: 3

Bravo AF: 0.0183

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.37
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

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: rs112278014; hg19: chr22-36649791;