22-36256991-C-T

Variant names:

• chr22-36256991-C-T
• rs141087521
• NM_003661.4:c.45-92C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003661.4(APOL1):​c.45-92C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000965 in 1,399,672 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: APOL1 NM_003661.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.141
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-36256991-C-T is Benign according to our data. Variant chr22-36256991-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1317542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000554 (691/1247354) while in subpopulation AFR AF = 0.0184 (531/28854). AF 95% confidence interval is 0.0171. There are 4 homozygotes in GnomAdExome4. There are 295 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.45-92C>T		intron	N/A	NP_003652.2
	APOL1	NM_145343.3		c.93-92C>T		intron	N/A	NP_663318.1	O14791-2
	APOL1	NM_001136540.2		c.45-92C>T		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.45-92C>T		intron	N/A	ENSP00000380448.4	O14791-1
	APOL1	ENST00000319136.8	TSL:1	c.93-92C>T		intron	N/A	ENSP00000317674.4	O14791-2
	APOL1	ENST00000438034.6	TSL:4	c.132-92C>T		intron	N/A	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 657 AN: 152200 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000554 AC: 691 AN: 1247354 Hom.: 4 AF XY: 0.000474 AC XY: 295 AN XY: 621892

African (AFR) AF: 0.0184 AC: 531 AN: 28854

American (AMR) AF: 0.00124 AC: 46 AN: 37074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22392

East Asian (EAS) AF: 0.00 AC: 0 AN: 37564

South Asian (SAS) AF: 0.000122 AC: 9 AN: 73966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50866

Middle Eastern (MID) AF: 0.000780 AC: 4 AN: 5126

European-Non Finnish (NFE) AF: 0.0000565 AC: 53 AN: 938660

Other (OTH) AF: 0.000908 AC: 48 AN: 52852

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152318 Hom.: 8 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74470

African (AFR) AF: 0.0150 AC: 622 AN: 41556

American (AMR) AF: 0.00144 AC: 22 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.00485

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.32
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141087521; hg19: chr22-36653037;