22-35658902-G-T

Variant names:

• chr22-35658902-G-T
• rs1446997257
• NM_030641.4:c.338G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030641.4(APOL6):​c.338G>T​(p.Gly113Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APOL6 NM_030641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

Genes affected

APOL6 (HGNC:14870): (apolipoprotein L6) This gene is a member of the apolipoprotein L gene family. The encoded protein is found in the cytoplasm, where it may affect the movement of lipids or allow the binding of lipids to organelles. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOL6	NM_030641.4	c.338G>T	p.Gly113Val	missense_variant	Exon 3 of 3	ENST00000409652.5	NP_085144.1
APOL6	XM_011530392.4	c.338G>T	p.Gly113Val	missense_variant	Exon 4 of 4		XP_011528694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOL6	ENST00000409652.5	c.338G>T	p.Gly113Val	missense_variant	Exon 3 of 3	1	NM_030641.4	ENSP00000386280.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250374 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135324

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338G>T (p.G113V) alteration is located in exon 3 (coding exon 2) of the APOL6 gene. This alteration results from a G to T substitution at nucleotide position 338, causing the glycine (G) at amino acid position 113 to be replaced by a valine (V). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.29
Sift	Benign	0.041	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.96		Loss of disorder (P = 0.0281);
MVP		0.67
MPC		0.74
ClinPred		0.94	D
GERP RS		3.1
Varity_R		0.44
gMVP		0.84

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: rs1446997257; hg19: chr22-36054949;