Genetic Variant APOL1:p.Leu10Met (chr22-36253990-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145343.3(APOL1):c.28T>A(p.Leu10Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

APOL1
NM_145343.3 missense, splice_region

Scores

Splicing: ADA: 0.0001882

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.48

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 4, susceptibility to
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

APOL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10315636).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL1	NM_003661.4	MANE Select	c.-20+771T>A		intron	N/A	NP_003652.2
APOL1	NM_145343.3		c.28T>A	p.Leu10Met	missense splice_region	Exon 2 of 7	NP_663318.1	O14791-2
APOL1	NM_001136540.2		c.-59+771T>A		intron	N/A	NP_001130012.1	O14791-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL1	ENST00000319136.8	TSL:1	c.28T>A	p.Leu10Met	missense splice_region	Exon 2 of 7	ENSP00000317674.4	O14791-2
APOL1	ENST00000397278.8	TSL:1 MANE Select	c.-20+771T>A		intron	N/A	ENSP00000380448.4	O14791-1
APOL1	ENST00000438034.6	TSL:4	c.28T>A	p.Leu10Met	missense splice_region	Exon 2 of 7	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.42

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.017

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.18

M_CAP

Benign

0.0013

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

PhyloP100

-1.5

PROVEAN

Benign

-0.060

REVEL

Benign

0.098

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.17

MutPred

0.29

Gain of catalytic residue at L10 (P = 0.0308)

MVP

0.067

MPC

0.30

ClinPred

0.33

GERP RS

-3.8

gMVP

0.052

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.17

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over