Variant chr17-42773812-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032353.4(VPS25):c.133A>C(p.Lys45Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,614,132 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: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

VPS25
NM_032353.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Variant links:

Genes affected

VPS25 (HGNC:28122): (vacuolar protein sorting 25 homolog) This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A pseudogene of this gene is present on chromosome 1. [provided by RefSeq, Jul 2013]

VPS25 links:

VPS25 (HGNC:):

VPS25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2846331).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS25	NM_032353.4 linkuse as main transcript	c.133A>C	p.Lys45Gln	missense_variant	2/6	ENST00000253794.7	NP_115729.1	Q9BRG1A0A024R1X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS25	ENST00000253794.7 linkuse as main transcript	c.133A>C	p.Lys45Gln	missense_variant	2/6	1	NM_032353.4	ENSP00000253794.1		Q9BRG1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000637

AC:

AN:

251344

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

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:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

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:

0.0000712

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Feb 23, 2023

The c.133A>C (p.K45Q) alteration is located in exon 2 (coding exon 2) of the VPS25 gene. This alteration results from a A to C substitution at nucleotide position 133, causing the lysine (K) at amino acid position 45 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.82

M_CAP

Benign

0.021

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.37

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.031

Polyphen

0.99

Vest4

0.43

MutPred

0.72

Loss of sheet (P = 0.007);

MVP

0.46

MPC

1.5

ClinPred

0.71

GERP RS

4.5

Varity_R

0.81

gMVP

0.67

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.

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