NM_016208.4:c.146T>C

Variant names:

• chr8-144425731-A-G
• NM_016208.4:c.146T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3111553).

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.146T>C	p.Met49Thr	missense	Exon 5 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.146T>C	p.Met49Thr	missense	Exon 5 of 9	NP_898880.1	Q9UK41-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	ENST00000292510.6	TSL:1 MANE Select	c.146T>C	p.Met49Thr	missense	Exon 5 of 10	ENSP00000292510.3	Q9UK41-1
	VPS28	ENST00000377348.6	TSL:1	c.146T>C	p.Met49Thr	missense	Exon 5 of 9	ENSP00000366565.2	Q9UK41-2
	VPS28	ENST00000526054.5	TSL:1	c.146T>C	p.Met49Thr	missense	Exon 4 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461608 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N
PhyloP100		5.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Benign	0.40	T
Sift4G	Benign	0.14	T
Polyphen		0.38	B
Vest4		0.73
MutPred		0.70		Loss of catalytic residue at V45 (P = 0.0407)
MVP		0.20
MPC		0.29
ClinPred		0.68	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.79
Mutation Taster		=38/62	disease causing

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

Other links and lift over

hg19: chr8-145651114;