Variant 15-42164372-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015289.5(VPS39):c.2012A>G(p.Asp671Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VPS39
NM_015289.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.26

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VPS39	NM_015289.5 linkuse as main transcript	c.2012A>G	p.Asp671Gly	missense_variant	19/25	ENST00000318006.10
VPS39	NM_001301138.3 linkuse as main transcript	c.2045A>G	p.Asp682Gly	missense_variant	20/26
VPS39	XM_011521403.3 linkuse as main transcript	c.2045A>G	p.Asp682Gly	missense_variant	20/26
VPS39	XM_011521404.3 linkuse as main transcript	c.2012A>G	p.Asp671Gly	missense_variant	19/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS39	ENST00000318006.10 linkuse as main transcript	c.2012A>G	p.Asp671Gly	missense_variant	19/25	1	NM_015289.5	P4	Q96JC1-2
VPS39	ENST00000348544.4 linkuse as main transcript	c.2045A>G	p.Asp682Gly	missense_variant	20/26	1		A1	Q96JC1-1
VPS39	ENST00000561818.1 linkuse as main transcript	n.355A>G		non_coding_transcript_exon_variant	1/2	3
VPS39	ENST00000562258.5 linkuse as main transcript	n.1506A>G		non_coding_transcript_exon_variant	2/8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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 06, 2022

The c.2012A>G (p.D671G) alteration is located in exon 19 (coding exon 19) of the VPS39 gene. This alteration results from a A to G substitution at nucleotide position 2012, causing the aspartic acid (D) at amino acid position 671 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

Benign

0.23

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.20

Sift

Benign

0.095

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.55

P;B

Vest4

0.88

MutPred

0.57

.;Gain of sheet (P = 0.0166);

MVP

0.53

MPC

0.34

ClinPred

0.79

GERP RS

6.1

Varity_R

0.30

gMVP

0.57

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