chr22-36265995-AATAATT-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4BA1
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
Consequence
NM_003661.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOL1 | NM_003661.4 | c.1164_1169delTTATAA | p.Asn388_Tyr389del | disruptive_inframe_deletion | Exon 6 of 6 | ENST00000397278.8 | NP_003652.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0388 AC: 5899AN: 152120Hom.: 410 Cov.: 31
GnomAD3 exomes AF: 0.00976 AC: 2429AN: 248746Hom.: 144 AF XY: 0.00713 AC XY: 961AN XY: 134836
GnomAD4 exome AF: 0.00369 AC: 5397AN: 1460676Hom.: 338 AF XY: 0.00303 AC XY: 2204AN XY: 726584
GnomAD4 genome AF: 0.0388 AC: 5908AN: 152238Hom.: 410 Cov.: 31 AF XY: 0.0378 AC XY: 2815AN XY: 74452
ClinVar
Submissions by phenotype
Focal segmental glomerulosclerosis 4, susceptibility to Pathogenic:1Other:2
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G2 -
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not provided Uncertain:1Benign:1
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This variant, c.1164_1169del, results in the deletion of 2 amino acid(s) of the APOL1 protein (p.Asn388_Tyr389del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs143830837, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This variant constitutes the “G2” allele of APOL1. This allele is associated with increased risk for several forms of kidney disease in individuals of African-American ancestry when present in homozygosity or in trans with the “G1” allele (which is composed of the c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met) variants in cis). Several large case-control studies have shown a 6- to 47-fold increased risk of focal segmental glomerulosclerosis, HIV-associated nephropathy, or non-diabetic end-stage kidney disease in individuals with homozygous G1, homozygous G2, or G1 in trans with G2 alleles (PMID: 20647424, 20635188, 21997394). Similar studies in African populations have generally recapitulated these findings, but these studies are based on a relatively small number of individuals (PMID: 30340464, 25788523). A recent PheWAS study also appears to support these findings, although the risk of end-stage kidney disease may be smaller than initially assumed (closer to 3- to 4-fold; PMID: 32247630). ClinVar contains an entry for this variant (Variation ID: 6081). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APOL1 function (PMID: 30332315, 32675303). In summary, this variant has been shown to confer an increased risk for kidney disease, either in homozygosity or in trans with the G1 allele. However, its significance when present in heterozygosity is unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance. -
Nephrotic range proteinuria Pathogenic:1
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Focal segmental glomerulosclerosis Pathogenic:1
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not specified Benign:1
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Hyalinosis, Segmental Glomerular Other:1
APOL1 c.1164_1169del (p.Asn388_Tyr389del), traditionally referred to as G1, has been associated with increased risk for multiple renal diseases in African Americans, particularly focal segmental glomerulosclerosis (FSGS), as well as an increased risk for end-stage kidney disease (ESKD). This variant is common in individuals of African ancestry (14%, Genome Aggregation Database (gnomAD); rs71785313) and is present in ClinVar (ID: 6081). Several small case-control studies have reported odds ratios between 3.92-25.1 for developing FSGS/HIVAN in homozygous individuals (OR=3.92 [95% CI 1.47-9.39] for FSGS/HIVAN Ito 2014, OR=14.4 [95% CI 1.7-116.3] for HIVAN, OR=25.1 [95% CI 8.8-83.3] for FSGS Kopp 2011, OR=5.69 [95% CI not given, P<0.00001] Limou 2015). In vitro and in vivo studies provide some evidence that these alleles impact protein function (Beckerman 2017, Hayek 2017). In summary, this variant is an established risk factor for chronic kidney disease in homozygous state. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at