rs2239785

chr22-36265284-G-Achr22-36265284-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003661.4(APOL1):c.448G>A(p.Glu150Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,690 control chromosomes in the GnomAD database, including 510,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.68 (38824 hom., cov: 31)
  • Exomes 𝑓: 0.80 (471605 hom.)
• Consequence: APOL1 NM_003661.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.258

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4776589E-6).
• BP6: Variant 22-36265284-G-A is Benign according to our data. Variant chr22-36265284-G-A is described in ClinVar as [Benign]. Clinvar id is 1168875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36265284-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOL1	NM_003661.4	c.448G>A	p.Glu150Lys	missense_variant	6/6	ENST00000397278.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOL1	ENST00000397278.8	c.448G>A	p.Glu150Lys	missense_variant	6/6	1	NM_003661.4	A2

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104059 AN: 151950 Hom.: 38808 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.721

GnomAD3 exomes AF: 0.791 AC: 198800 AN: 251180 Hom.: 80607 AF XY: 0.797 AC XY: 108255 AN XY: 135778

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.818

Gnomad EAS exome AF: 0.834

Gnomad SAS exome AF: 0.815

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.805

GnomAD4 exome AF: 0.800 AC: 1168760 AN: 1461622 Hom.: 471605 Cov.: 76 AF XY: 0.800 AC XY: 582048 AN XY: 727150

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.874

Gnomad4 ASJ exome AF: 0.821

Gnomad4 EAS exome AF: 0.833

Gnomad4 SAS exome AF: 0.816

Gnomad4 FIN exome AF: 0.842

Gnomad4 NFE exome AF: 0.807

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.685 AC: 104116 AN: 152068 Hom.: 38824 Cov.: 31 AF XY: 0.694 AC XY: 51587 AN XY: 74340

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.816

Gnomad4 ASJ AF: 0.812

Gnomad4 EAS AF: 0.824

Gnomad4 SAS AF: 0.823

Gnomad4 FIN AF: 0.842

Gnomad4 NFE AF: 0.799

Gnomad4 OTH AF: 0.723

Alfa AF: 0.778 Hom.: 90634

Bravo AF: 0.669

TwinsUK AF: 0.811 AC: 3006

ALSPAC AF: 0.807 AC: 3109

ESP6500AA AF: 0.374 AC: 1647

ESP6500EA AF: 0.796 AC: 6844

ExAC AF: 0.780 AC: 94686

Asia WGS AF: 0.811 AC: 2817 AN: 3478

EpiCase AF: 0.785

EpiControl AF: 0.791

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 19239905, 22239288) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.018	T;T;.;.;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0086	N
MetaRNN	Benign	0.0000025	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;.;.;.;L
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.43	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;.;D
Vest4		0.10
MPC		0.35
ClinPred		0.028	T
GERP RS		-2.2
Varity_R		0.035
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239785; hg19: chr22-36661330; COSMIC: COSV59868177; COSMIC: COSV59868177;