15-42163674-G-C

Position:

• chr15-42163674-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015289.5(VPS39):​c.2081C>G​(p.Ala694Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 33)
• Consequence: VPS39 NM_015289.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

VPS39 (HGNC:20593): (VPS39 subunit of HOPS complex) This gene encodes a protein that may promote clustering and fusion of late endosomes and lysosomes. The protein may also act as an adaptor protein that modulates the transforming growth factor-beta response by coupling the transforming growth factor-beta receptor complex to the Smad pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS39	NM_015289.5	c.2081C>G	p.Ala694Gly	missense_variant	20/25	ENST00000318006.10	NP_056104.2
VPS39	NM_001301138.3	c.2114C>G	p.Ala705Gly	missense_variant	21/26		NP_001288067.1
VPS39	XM_011521403.3	c.2114C>G	p.Ala705Gly	missense_variant	21/26		XP_011519705.1
VPS39	XM_011521404.3	c.2081C>G	p.Ala694Gly	missense_variant	20/25		XP_011519706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS39	ENST00000318006.10	c.2081C>G	p.Ala694Gly	missense_variant	20/25	1	NM_015289.5	ENSP00000326534	P4
VPS39	ENST00000348544.4	c.2114C>G	p.Ala705Gly	missense_variant	21/26	1		ENSP00000335193	A1
VPS39	ENST00000561818.1	n.424C>G		non_coding_transcript_exon_variant	2/2	3
VPS39	ENST00000562258.5	n.1575C>G		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Nov 03, 2022

The c.2081C>G (p.A694G) alteration is located in exon 20 (coding exon 20) of the VPS39 gene. This alteration results from a C to G substitution at nucleotide position 2081, causing the alanine (A) at amino acid position 694 to be replaced by a glycine (G). 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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.6	.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.65		.;Loss of helix (P = 0.0072);
MVP		0.87
MPC		0.65
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42455872;