Variant 15-42164480-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000318006.10(VPS39):c.1904C>G(p.Thr635Ser) variant causes a missense change involving the alteration of a non-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. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T635P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VPS39
ENST00000318006.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

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:

VPS39 (HGNC:):

VPS39 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06534809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS39	NM_015289.5 linkuse as main transcript	c.1904C>G	p.Thr635Ser	missense_variant	19/25	ENST00000318006.10	NP_056104.2	Q96JC1-2A0A024R9L9
VPS39	NM_001301138.3 linkuse as main transcript	c.1937C>G	p.Thr646Ser	missense_variant	20/26		NP_001288067.1	Q96JC1-1
VPS39	XM_011521403.3 linkuse as main transcript	c.1937C>G	p.Thr646Ser	missense_variant	20/26		XP_011519705.1
VPS39	XM_011521404.3 linkuse as main transcript	c.1904C>G	p.Thr635Ser	missense_variant	19/25		XP_011519706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VPS39	ENST00000318006.10 linkuse as main transcript	c.1904C>G	p.Thr635Ser	missense_variant	19/25	1	NM_015289.5	ENSP00000326534.5	Q96JC1-2
VPS39	ENST00000348544.4 linkuse as main transcript	c.1937C>G	p.Thr646Ser	missense_variant	20/26	1		ENSP00000335193.5	Q96JC1-1
VPS39	ENST00000561818.1 linkuse as main transcript	n.247C>G		non_coding_transcript_exon_variant	1/2	3
VPS39	ENST00000562258.5 linkuse as main transcript	n.1398C>G		non_coding_transcript_exon_variant	2/8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251196

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135762

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

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.:

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

Jul 11, 2023

The c.1904C>G (p.T635S) alteration is located in exon 19 (coding exon 19) of the VPS39 gene. This alteration results from a C to G substitution at nucleotide position 1904, causing the threonine (T) at amino acid position 635 to be replaced by a serine (S). 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

0.071

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.029

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.051

Sift

Benign

0.86

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.0

B;B

Vest4

0.21

MutPred

0.33

.;Gain of disorder (P = 0.0312);

MVP

0.33

MPC

0.13

ClinPred

0.015

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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