chr22-36142057-C-G

Position:

• chr22-36142057-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145639.2(APOL3):​c.139G>C​(p.Asp47His) 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. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APOL3 NM_145639.2 missense, splice_region
• Scores: Splicing: ADA: 0.0004008
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.185

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.303428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOL3	NM_145639.2	c.139G>C	p.Asp47His	missense_variant, splice_region_variant	4/4	ENST00000424878.4	NP_663614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOL3	ENST00000424878.4	c.139G>C	p.Asp47His	missense_variant, splice_region_variant	4/4	1	NM_145639.2	ENSP00000415779	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.352G>C (p.D118H) alteration is located in exon 3 (coding exon 3) of the APOL3 gene. This alteration results from a G to C substitution at nucleotide position 352, causing the aspartic acid (D) at amino acid position 118 to be replaced by a histidine (H). 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	0.32
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	D;D
Vest4		0.10
MutPred		0.67		Loss of stability (P = 0.1052);.;
MVP		0.45
MPC		0.69
ClinPred		0.63	D
GERP RS		0.43
Varity_R		0.24
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.032
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: rs1368496459; hg19: chr22-36538105;