Variant 15-42163693-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015289.5(VPS39):c.2062A>G(p.Met688Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

VPS39
NM_015289.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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]

VPS39 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS39	NM_015289.5 linkuse as main transcript	c.2062A>G	p.Met688Val	missense_variant	20/25	ENST00000318006.10	NP_056104.2
VPS39	NM_001301138.3 linkuse as main transcript	c.2095A>G	p.Met699Val	missense_variant	21/26		NP_001288067.1
VPS39	XM_011521403.3 linkuse as main transcript	c.2095A>G	p.Met699Val	missense_variant	21/26		XP_011519705.1
VPS39	XM_011521404.3 linkuse as main transcript	c.2062A>G	p.Met688Val	missense_variant	20/25		XP_011519706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS39	ENST00000318006.10 linkuse as main transcript	c.2062A>G	p.Met688Val	missense_variant	20/25	1	NM_015289.5	ENSP00000326534	P4	Q96JC1-2
VPS39	ENST00000348544.4 linkuse as main transcript	c.2095A>G	p.Met699Val	missense_variant	21/26	1		ENSP00000335193	A1	Q96JC1-1
VPS39	ENST00000561818.1 linkuse as main transcript	n.405A>G		non_coding_transcript_exon_variant	2/2	3
VPS39	ENST00000562258.5 linkuse as main transcript	n.1556A>G		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250642

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135468

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

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 submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.2062A>G (p.M688V) alteration is located in exon 20 (coding exon 20) of the VPS39 gene. This alteration results from a A to G substitution at nucleotide position 2062, causing the methionine (M) at amino acid position 688 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

Benign

0.30

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.054

.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.22

Sift

Benign

0.16

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.020

B;B

Vest4

0.82

MVP

0.41

MPC

0.16

ClinPred

0.40

GERP RS

5.6

Varity_R

0.26

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over