15-42164469-C-T

Position:

• chr15-42164469-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000318006.10(VPS39):​c.1915G>A​(p.Ala639Thr) 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 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. A639D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS39 ENST00000318006.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4139998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS39	NM_015289.5	c.1915G>A	p.Ala639Thr	missense_variant	19/25	ENST00000318006.10	NP_056104.2
VPS39	NM_001301138.3	c.1948G>A	p.Ala650Thr	missense_variant	20/26		NP_001288067.1
VPS39	XM_011521403.3	c.1948G>A	p.Ala650Thr	missense_variant	20/26		XP_011519705.1
VPS39	XM_011521404.3	c.1915G>A	p.Ala639Thr	missense_variant	19/25		XP_011519706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS39	ENST00000318006.10	c.1915G>A	p.Ala639Thr	missense_variant	19/25	1	NM_015289.5	ENSP00000326534.5
VPS39	ENST00000348544.4	c.1948G>A	p.Ala650Thr	missense_variant	20/26	1		ENSP00000335193.5
VPS39	ENST00000561818.1	n.258G>A		non_coding_transcript_exon_variant	1/2	3
VPS39	ENST00000562258.5	n.1409G>A		non_coding_transcript_exon_variant	2/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 19, 2023

The c.1915G>A (p.A639T) alteration is located in exon 19 (coding exon 19) of the VPS39 gene. This alteration results from a G to A substitution at nucleotide position 1915, causing the alanine (A) at amino acid position 639 to be replaced by a threonine (T). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	.;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.23	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.035	B;B
Vest4		0.65
MutPred		0.41		.;Gain of glycosylation at A650 (P = 0.0068);
MVP		0.60
MPC		0.22
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42456667;