22-36195390-C-G

Variant names:

• chr22-36195390-C-G
• rs1046098637
• NM_001386885.1:c.130G>C

Variant summary

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

The NM_001386885.1(APOL4):​c.130G>C​(p.Val44Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: APOL4 NM_001386885.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.15
• Publications: 0 publications found

Genes affected

APOL4 (HGNC:14867): (apolipoprotein L4) This gene encodes a member of the apolipoprotein L family. The encoded protein 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2020]

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_001386885.1. 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
	APOL4	NM_001386885.1	MANE Select	c.130G>C	p.Val44Leu	missense	Exon 3 of 4	NP_001373814.1	Q9BPW4-2
	APOL4	NM_145660.2		c.139G>C	p.Val47Leu	missense	Exon 4 of 5	NP_663693.1	Q9BPW4-1
	APOL4	NM_030643.4		c.130G>C	p.Val44Leu	missense	Exon 5 of 6	NP_085146.2	Q9BPW4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOL4	ENST00000683024.1	MANE Select	c.130G>C	p.Val44Leu	missense	Exon 3 of 4	ENSP00000507418.1	Q9BPW4-2
	APOL4	ENST00000352371.5	TSL:1	c.139G>C	p.Val47Leu	missense	Exon 4 of 5	ENSP00000338260.3	Q9BPW4-1
	APOL4	ENST00000616056.4	TSL:1	c.130G>C	p.Val44Leu	missense	Exon 5 of 6	ENSP00000483497.1	Q9BPW4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250230 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461504 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44708

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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	0.71
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.75
DANN	Benign	0.34
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.078
Sift	Benign	0.086	T
Sift4G	Uncertain	0.034	D
Polyphen		0.081	B
Vest4		0.036
MutPred		0.85		Loss of methylation at K46 (P = 0.041)
MVP		0.26
MPC		0.099
ClinPred		0.097	T
GERP RS		-4.1
Varity_R		0.065
gMVP		0.099
Mutation Taster		=100/0	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: rs1046098637; hg19: chr22-36591436;