Variant 8-144425731-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016208.4(VPS28):c.146T>C(p.Met49Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,608 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: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

VPS28
NM_016208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02

Variant links:

Genes affected

VPS28 (HGNC:18178): (VPS28 subunit of ESCRT-I) This gene encodes a protein subunit of the ESCRT-I complex (endosomal complexes required for transport), which functions in the transport and sorting of proteins into subcellular vesicles. This complex can also be hijacked to facilitate the budding of enveloped viruses from the cell membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

VPS28 links:

VPS28 (HGNC:):

VPS28 links:

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ACMG classification

Classification made for transcript

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=0.3111553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS28	NM_016208.4 linkuse as main transcript	c.146T>C	p.Met49Thr	missense_variant	5/10	ENST00000292510.6	NP_057292.1	Q9UK41-1Q548N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS28	ENST00000292510.6 linkuse as main transcript	c.146T>C	p.Met49Thr	missense_variant	5/10	1	NM_016208.4	ENSP00000292510.3		Q9UK41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Jun 07, 2024

The c.146T>C (p.M49T) alteration is located in exon 5 (coding exon 4) of the VPS28 gene. This alteration results from a T to C substitution at nucleotide position 146, causing the methionine (M) at amino acid position 49 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

0.43

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.10

.;T;.;T;T;.;.

Eigen

Benign

-0.073

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.0044

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.97

N;N;N;N;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

N;N;N;N;N;N;D

REVEL

Benign

0.26

Sift

Benign

0.40

T;T;T;T;T;D;D

Sift4G

Benign

0.14

T;T;T;T;.;.;D

Polyphen

0.38

B;B;B;B;.;.;.

Vest4

0.73

MutPred

0.70

Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);Loss of catalytic residue at V45 (P = 0.0407);

MVP

0.20

MPC

0.29

ClinPred

0.68

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over