rs371861006

Variant names:

• chr8-144424072-C-A
• rs371861006
• NM_016208.4:c.517G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144424072-C-A
• chr8-144424072-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016208.4(VPS28):​c.517G>T​(p.Asp173Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,414,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D173N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: VPS28 NM_016208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

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.517G>T	p.Asp173Tyr	missense	Exon 9 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.517G>T	p.Asp173Tyr	missense	Exon 9 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.517G>T	p.Asp173Tyr	missense	Exon 9 of 10	ENSP00000292510.3	Q9UK41-1
	VPS28	ENST00000377348.6	TSL:1	c.517G>T	p.Asp173Tyr	missense	Exon 9 of 9	ENSP00000366565.2	Q9UK41-2
	VPS28	ENST00000526054.5	TSL:1	c.517G>T	p.Asp173Tyr	missense	Exon 8 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414422 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 696824

African (AFR) AF: 0.00 AC: 0 AN: 32670

American (AMR) AF: 0.00 AC: 0 AN: 41636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39144

South Asian (SAS) AF: 0.00 AC: 0 AN: 78806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084820

Other (OTH) AF: 0.00 AC: 0 AN: 58320

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.66		Gain of catalytic residue at D173 (P = 0.0174)
MVP		0.20
MPC		0.17
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.92
Mutation Taster		=12/88	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: rs371861006; hg19: chr8-145649455;