15-42166635-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015289.5(VPS39):​c.1534G>A​(p.Val512Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

VPS39
NM_015289.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.46
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20367518).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS39NM_015289.5 linkuse as main transcriptc.1534G>A p.Val512Met missense_variant 15/25 ENST00000318006.10 NP_056104.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS39ENST00000318006.10 linkuse as main transcriptc.1534G>A p.Val512Met missense_variant 15/251 NM_015289.5 ENSP00000326534 P4Q96JC1-2
VPS39ENST00000348544.4 linkuse as main transcriptc.1567G>A p.Val523Met missense_variant 16/261 ENSP00000335193 A1Q96JC1-1
VPS39ENST00000563692.1 linkuse as main transcriptn.119G>A non_coding_transcript_exon_variant 2/64

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251288
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135810
show subpopulations
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:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 16, 2022The c.1534G>A (p.V512M) alteration is located in exon 15 (coding exon 15) of the VPS39 gene. This alteration results from a G to A substitution at nucleotide position 1534, causing the valine (V) at amino acid position 512 to be replaced by a methionine (M). 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
0.11
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.041
.;T
Eigen
Benign
0.035
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.14
.;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
0.40
N;N
REVEL
Benign
0.073
Sift
Benign
0.17
T;T
Sift4G
Benign
0.17
T;T
Polyphen
0.075
B;B
Vest4
0.36
MutPred
0.61
.;Gain of disorder (P = 0.0953);
MVP
0.38
MPC
0.94
ClinPred
0.45
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.066
gMVP
0.21

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1413010645; hg19: chr15-42458833; API