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GeneBe

22-36141214-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145639.2(APOL3):c.982T>C(p.Cys328Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APOL3
NM_145639.2 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.42
Variant links:
Genes affected
APOL3 (HGNC:14868): (apolipoprotein L3) This gene is a member of the apolipoprotein L gene family, and it is present in a cluster with other family members on chromosome 22. The encoded protein is found in the cytoplasm, where it may affect the movement of lipids, including cholesterol, and/or allow the binding of lipids to organelles. In addition, expression of this gene is up-regulated by tumor necrosis factor-alpha in endothelial cells lining the normal and atherosclerotic iliac artery and aorta. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05985114).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APOL3NM_145639.2 linkuse as main transcriptc.982T>C p.Cys328Arg missense_variant 4/4 ENST00000424878.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOL3ENST00000424878.4 linkuse as main transcriptc.982T>C p.Cys328Arg missense_variant 4/41 NM_145639.2 A2O95236-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461268
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726910
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 20, 2023The c.1195T>C (p.C399R) alteration is located in exon 3 (coding exon 3) of the APOL3 gene. This alteration results from a T to C substitution at nucleotide position 1195, causing the cysteine (C) at amino acid position 399 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.75
Cadd
Benign
0.50
Dann
Benign
0.30
DEOGEN2
Benign
0.00059
T;.;.;.;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.0094
N
LIST_S2
Benign
0.21
T;T;.;.;T
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.060
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.0
N;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.030
N;.;N;N;.
REVEL
Benign
0.044
Sift
Benign
0.077
T;.;T;T;.
Polyphen
0.48
P;.;.;.;P
Vest4
0.073
MutPred
0.36
Gain of MoRF binding (P = 2e-04);.;.;.;.;
MVP
0.092
MPC
0.45
ClinPred
0.26
T
GERP RS
-1.8
Varity_R
0.13
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs764737986; hg19: chr22-36537262; API