chr8-144424956-C-T

Variant names:

• chr8-144424956-C-T
• rs781982468
• NM_016208.4:c.290G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016208.4(VPS28):​c.290G>A​(p.Arg97His) variant causes a missense change. The variant allele was found at a frequency of 0.0000324 in 1,572,854 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: VPS28 NM_016208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2419807).

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.290G>A	p.Arg97His	missense	Exon 6 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.290G>A	p.Arg97His	missense	Exon 6 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.290G>A	p.Arg97His	missense	Exon 6 of 10	ENSP00000292510.3	Q9UK41-1
	VPS28	ENST00000377348.6	TSL:1	c.290G>A	p.Arg97His	missense	Exon 6 of 9	ENSP00000366565.2	Q9UK41-2
	VPS28	ENST00000526054.5	TSL:1	c.290G>A	p.Arg97His	missense	Exon 5 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000275 AC: 5 AN: 181816 AF XY: 0.0000103

Gnomad AFR exome AF: 0.0000916

Gnomad AMR exome AF: 0.0000758

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.0000211 AC: 30 AN: 1420672 Hom.: 0 Cov.: 33 AF XY: 0.0000228 AC XY: 16 AN XY: 703200

African (AFR) AF: 0.00 AC: 0 AN: 32574

American (AMR) AF: 0.0000534 AC: 2 AN: 37446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25394

East Asian (EAS) AF: 0.000186 AC: 7 AN: 37598

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000165 AC: 18 AN: 1090196

Other (OTH) AF: 0.0000340 AC: 2 AN: 58872

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74342

African (AFR) AF: 0.000193 AC: 8 AN: 41446

American (AMR) AF: 0.000785 AC: 12 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000252 AC: 3

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	Benign	0.13
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.057	T
Polyphen		0.048	B
Vest4		0.39
MVP		0.22
MPC		0.22
ClinPred		0.39	T
GERP RS		5.5
Varity_R		0.66
gMVP		0.50
Mutation Taster		=41/59	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

dbSNP: rs781982468; hg19: chr8-145650339; COSMIC: COSV99465647; COSMIC: COSV99465647;