NM_003661.4:c.23G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003661.4(APOL1):c.23G>A(p.Arg8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APOL1
NM_003661.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.355

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011082053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOL1	NM_003661.4 link	c.23G>A	p.Arg8Lys	missense_variant	Exon 2 of 6	ENST00000397278.8	NP_003652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOL1	ENST00000397278.8 link	c.23G>A	p.Arg8Lys	missense_variant	Exon 2 of 6	1	NM_003661.4	ENSP00000380448.4		O14791-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

156

AN:

151060

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251348

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000315

AC:

AN:

1459084

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

725974

show subpopulations

Gnomad4 AFR exome

AF:

0.000819

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00103

AC:

156

AN:

151184

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

AN XY:

73954

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.00276

Hom.:

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1432755). This variant has not been reported in the literature in individuals affected with APOL1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 8 of the APOL1 protein (p.Arg8Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.9

DANN

Benign

0.91

DEOGEN2

Benign

0.0070

T;T;.;.;T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.43

.;.;T;T;T;T;T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;.;.;.;N;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.33

N;N;N;N;N;N;N;D

REVEL

Benign

0.062

Sift

Benign

0.17

T;T;T;T;D;T;T;D

Sift4G

Benign

0.35

T;T;T;T;D;T;T;D

Polyphen

0.78

P;P;.;P;.;.;P;.

Vest4

0.33

MVP

0.30

MPC

0.21

ClinPred

0.065

GERP RS

-2.3

Varity_R

0.082

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over