8-144426038-C-T

Variant names:

• chr8-144426038-C-T
• rs1393877832
• NM_016208.4:c.92G>A

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS28	NM_016208.4	c.92G>A	p.Arg31Gln	missense_variant	Exon 4 of 10	ENST00000292510.6	NP_057292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS28	ENST00000292510.6	c.92G>A	p.Arg31Gln	missense_variant	Exon 4 of 10	1	NM_016208.4	ENSP00000292510.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000133 AC: 2 AN: 150622 Hom.: 0 AF XY: 0.0000126 AC XY: 1 AN XY: 79386

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 SAS exome AF: 0.0000459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 20 AN: 1376528 Hom.: 0 Cov.: 32 AF XY: 0.0000148 AC XY: 10 AN XY: 674850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000568

Gnomad4 SAS exome AF: 0.0000256

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000132

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92G>A (p.R31Q) alteration is located in exon 4 (coding exon 3) of the VPS28 gene. This alteration results from a G to A substitution at nucleotide position 92, causing the arginine (R) at amino acid position 31 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	.;T;.;T;T;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Benign	0.040	D;D;D;D;D;T;D
Sift4G	Benign	0.12	T;T;T;T;.;.;D
Polyphen		1.0	D;D;D;D;.;.;.
Vest4		0.27
MutPred		0.34		Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);Gain of ubiquitination at K28 (P = 0.0482);
MVP		0.35
MPC		0.57
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs1393877832; hg19: chr8-145651421;