22-36254862-CAA-CA

Variant names:

• chr22-36254862-CA-C
• rs199714563
• NM_003661.4:c.-19-65delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003661.4(APOL1):​c.-19-65delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,391,308 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: APOL1 NM_003661.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.00316) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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.-19-65delA		intron	N/A	NP_003652.2
	APOL1	NM_145343.3		c.30-65delA		intron	N/A	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.-58-26delA		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.-19-74delA		intron	N/A	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.30-74delA		intron	N/A	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.30-35delA		intron	N/A	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.0000337 AC: 5 AN: 148496 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00320 AC: 497 AN: 155440 AF XY: 0.00323

Gnomad AFR exome AF: 0.000868

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00212

Gnomad FIN exome AF: 0.000623

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00190 AC: 2359 AN: 1242812 Hom.: 0 Cov.: 27 AF XY: 0.00187 AC XY: 1162 AN XY: 619972

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00174 AC: 50 AN: 28786

American (AMR) AF: 0.00151 AC: 58 AN: 38498

Ashkenazi Jewish (ASJ) AF: 0.00252 AC: 55 AN: 21858

East Asian (EAS) AF: 0.00369 AC: 123 AN: 33368

South Asian (SAS) AF: 0.00125 AC: 94 AN: 75108

European-Finnish (FIN) AF: 0.00178 AC: 83 AN: 46578

Middle Eastern (MID) AF: 0.00216 AC: 9 AN: 4166

European-Non Finnish (NFE) AF: 0.00187 AC: 1766 AN: 943194

Other (OTH) AF: 0.00236 AC: 121 AN: 51256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000337 AC: 5 AN: 148496 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72358

African (AFR) AF: 0.0000494 AC: 2 AN: 40500

American (AMR) AF: 0.00 AC: 0 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5100

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66800

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.0112 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
BranchPoint Hunter		1.0
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: rs199714563; hg19: chr22-36650908; COSMIC: COSV59869156;