NM_145639.2:c.488G>A

Variant names:

• chr22-36141708-C-T
• rs1603474386
• NM_145639.2:c.488G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145639.2(APOL3):​c.488G>A​(p.Gly163Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: APOL3 NM_145639.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.544
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL3	NM_145639.2	MANE Select	c.488G>A	p.Gly163Glu	missense	Exon 4 of 4	NP_663614.1	O95236-2
	APOL3	NM_145640.2		c.701G>A	p.Gly234Glu	missense	Exon 3 of 3	NP_663615.1	O95236-1
	APOL3	NM_001393587.1		c.491G>A	p.Gly164Glu	missense	Exon 5 of 5	NP_001380516.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL3	ENST00000424878.4	TSL:1 MANE Select	c.488G>A	p.Gly163Glu	missense	Exon 4 of 4	ENSP00000415779.3	O95236-2
	APOL3	ENST00000349314.7	TSL:1	c.701G>A	p.Gly234Glu	missense	Exon 3 of 3	ENSP00000344577.2	O95236-1
	APOL3	ENST00000361710.6	TSL:1	c.101G>A	p.Gly34Glu	missense	Exon 4 of 4	ENSP00000355164.2	O95236-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461726 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0073	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.54
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Sift4G	Benign	0.14	T
Polyphen		0.95	P
Vest4		0.20
MutPred		0.82		Gain of disorder (P = 0.0725)
MVP		0.26
MPC		0.70
ClinPred		0.85	D
GERP RS		3.3
Varity_R		0.25
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1603474386; hg19: chr22-36537756;