Genetic Variant VPS28:p.Arg31Gln (chr8-144426038-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016208.4(VPS28):c.92G>A(p.Arg31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,376,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

VPS28
NM_016208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.91

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	NM_016208.4	MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 4 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.92G>A	p.Arg31Gln	missense	Exon 4 of 9	NP_898880.1	Q9UK41-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS28	ENST00000292510.6	TSL:1 MANE Select	c.92G>A	p.Arg31Gln	missense	Exon 4 of 10	ENSP00000292510.3	Q9UK41-1
VPS28	ENST00000377348.6	TSL:1	c.92G>A	p.Arg31Gln	missense	Exon 4 of 9	ENSP00000366565.2	Q9UK41-2
VPS28	ENST00000526054.5	TSL:1	c.92G>A	p.Arg31Gln	missense	Exon 3 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

150622

AF XY:

0.0000126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000890

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1376528

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

674850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31068

American (AMR)

AF:

0.0000296

AC:

AN:

33838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24318

East Asian (EAS)

AF:

0.0000568

AC:

AN:

35228

South Asian (SAS)

AF:

0.0000256

AC:

AN:

78012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

0.0000132

AC:

AN:

1062942

Other (OTH)

AF:

0.0000176

AC:

AN:

56810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.4

PhyloP100

2.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.26

Sift

Benign

0.040

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.27

MutPred

0.34

Gain of ubiquitination at K28 (P = 0.0482)

MVP

0.35

MPC

0.57

ClinPred

0.91

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.47

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over