Genetic Variant NM_145639.2:c.446C>T (chr22-36141750-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145639.2(APOL3):c.446C>T(p.Thr149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,614,122 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 42 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

APOL3
NM_145639.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0630

Publications

6 publications found

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]

APOL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046978593).

BP6

Variant 22-36141750-G-A is Benign according to our data. Variant chr22-36141750-G-A is described in ClinVar as Benign. ClinVar VariationId is 784420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1865/152330) while in subpopulation AFR AF = 0.0425 (1768/41578). AF 95% confidence interval is 0.0409. There are 42 homozygotes in GnomAd4. There are 870 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145639.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL3	NM_145639.2	MANE Select	c.446C>T	p.Thr149Ile	missense	Exon 4 of 4	NP_663614.1	O95236-2
APOL3	NM_145640.2		c.659C>T	p.Thr220Ile	missense	Exon 3 of 3	NP_663615.1	O95236-1
APOL3	NM_001393587.1		c.449C>T	p.Thr150Ile	missense	Exon 5 of 5	NP_001380516.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOL3	ENST00000424878.4	TSL:1 MANE Select	c.446C>T	p.Thr149Ile	missense	Exon 4 of 4	ENSP00000415779.3	O95236-2
APOL3	ENST00000349314.7	TSL:1	c.659C>T	p.Thr220Ile	missense	Exon 3 of 3	ENSP00000344577.2	O95236-1
APOL3	ENST00000361710.6	TSL:1	c.59C>T	p.Thr20Ile	missense	Exon 4 of 4	ENSP00000355164.2	O95236-3

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1860

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00333

AC:

834

AN:

250644

AF XY:

0.00236

show subpopulations

Gnomad AFR exome

AF:

0.0439

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00136

AC:

1994

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

876

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0473

AC:

1585

AN:

33480

American (AMR)

AF:

0.00233

AC:

104

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000656

AC:

AN:

1111984

Other (OTH)

AF:

0.00252

AC:

152

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

131

262

394

525

656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0122

AC:

1865

AN:

152330

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

870

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0425

AC:

1768

AN:

41578

American (AMR)

AF:

0.00360

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68032

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

182

273

364

455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00473

Hom.:

Bravo

AF:

0.0139

ESP6500AA

AF:

0.0447

AC:

197

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00386

AC:

469

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.4

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.063

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.064

Sift

Benign

0.26

Sift4G

Benign

0.095

Polyphen

0.82

Vest4

0.25

MVP

0.24

MPC

0.67

ClinPred

0.030

GERP RS

-1.7

Varity_R

0.091

gMVP

0.51

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over