22-36141727-C-T

Position:

• chr22-36141727-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145639.2(APOL3):​c.469G>A​(p.Ala157Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,056 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (89 hom.)
• Consequence: APOL3 NM_145639.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064413548).
• BP6: Variant 22-36141727-C-T is Benign according to our data. Variant chr22-36141727-C-T is described in ClinVar as [Benign]. Clinvar id is 774970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00323 (492/152358) while in subpopulation SAS AF= 0.0284 (137/4824). AF 95% confidence interval is 0.0245. There are 5 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOL3	NM_145639.2	c.469G>A	p.Ala157Thr	missense_variant	4/4	ENST00000424878.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOL3	ENST00000424878.4	c.469G>A	p.Ala157Thr	missense_variant	4/4	1	NM_145639.2	A2

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152240 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00661 AC: 1654 AN: 250386 Hom.: 24 AF XY: 0.00828 AC XY: 1120 AN XY: 135340

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0312

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00451 AC: 6592 AN: 1461698 Hom.: 89 Cov.: 36 AF XY: 0.00546 AC XY: 3967 AN XY: 727144

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.000338

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00629

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152358 Hom.: 5 Cov.: 33 AF XY: 0.00360 AC XY: 268 AN XY: 74512

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00392 Hom.: 2

Bravo AF: 0.00265

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00693 AC: 841

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00558

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0090
DANN	Benign	0.79
DEOGEN2	Benign	0.0097	T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.43	T;T;.;.;T
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.56	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N;.;N;N;.
REVEL	Benign	0.074
Sift	Benign	0.17	T;.;T;T;.
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.79	P;.;.;.;P
Vest4		0.096
MVP		0.13
MPC		0.17
ClinPred		0.0034	T
GERP RS		-0.31
Varity_R		0.051
gMVP		0.28

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

Other links and lift over

dbSNP: rs142057520; hg19: chr22-36537775;