22-36254862-CAA-CAAAAA

Variant names:

• chr22-36254862-C-CAAA
• rs199714563
• NM_003661.4:c.-19-67_-19-65dupAAA

Variant summary

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

The NM_003661.4(APOL1):​c.-19-67_-19-65dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000079 in 1,266,470 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: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (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: Very rare variant in population databases, with high coverage

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.-19-67_-19-65dupAAA		intron	N/A	NP_003652.2
	APOL1	NM_145343.3		c.30-67_30-65dupAAA		intron	N/A	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.-58-28_-58-26dupAAA		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.-19-75_-19-74insAAA		intron	N/A	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.30-75_30-74insAAA		intron	N/A	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.30-36_30-35insAAA		intron	N/A	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1266470 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 631950

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

African (AFR) AF: 0.0000342 AC: 1 AN: 29282

American (AMR) AF: 0.00 AC: 0 AN: 39510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22386

East Asian (EAS) AF: 0.00 AC: 0 AN: 34114

South Asian (SAS) AF: 0.00 AC: 0 AN: 76834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 960422

Other (OTH) AF: 0.00 AC: 0 AN: 52326

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
BranchPoint Hunter		1.0

Splicing

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

Other links and lift over

dbSNP: rs199714563; hg19: chr22-36650908;