Variant 8-144426199-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016208.4(VPS28):c.47A>G(p.Asn16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,452,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

VPS28
NM_016208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.74

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1742948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS28	NM_016208.4 linkuse as main transcript	c.47A>G	p.Asn16Ser	missense_variant	3/10	ENST00000292510.6	NP_057292.1	Q9UK41-1Q548N1
VPS28	NM_183057.3 linkuse as main transcript	c.47A>G	p.Asn16Ser	missense_variant	3/9		NP_898880.1	Q9UK41-2
VPS28	XM_005272324.4 linkuse as main transcript	c.47A>G	p.Asn16Ser	missense_variant	3/10		XP_005272381.1	A0A0S2Z5H5
VPS28	XM_047421845.1 linkuse as main transcript	c.-172A>G		5_prime_UTR_variant	2/9		XP_047277801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS28	ENST00000292510.6 linkuse as main transcript	c.47A>G	p.Asn16Ser	missense_variant	3/10	1	NM_016208.4	ENSP00000292510.3		Q9UK41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000846

AC:

AN:

236324

Hom.:

AF XY:

0.00000779

AC XY:

AN XY:

128434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000608

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:

0.00

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1452880

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000460

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:

0.00000361

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

May 11, 2022

The c.47A>G (p.N16S) alteration is located in exon 3 (coding exon 2) of the VPS28 gene. This alteration results from a A to G substitution at nucleotide position 47, causing the asparagine (N) at amino acid position 16 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

0.067

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

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

Eigen

Benign

0.037

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.0046

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;L;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.2

N;N;N;N;N;N;N

REVEL

Benign

0.069

Sift

Benign

0.098

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

Sift4G

Benign

0.063

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

Polyphen

0.83

P;B;P;B;.;.;.

Vest4

0.55

MutPred

0.23

Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);Loss of catalytic residue at N16 (P = 3e-04);

MVP

0.36

MPC

0.29

ClinPred

0.38

GERP RS

5.1

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.69

gMVP

0.17

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