8-144426195-C-G

Variant names:

• chr8-144426195-C-G
• NM_016208.4:c.51G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016208.4(VPS28):​c.51G>C​(p.Lys17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS28 NM_016208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.386

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14721403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS28	NM_016208.4	c.51G>C	p.Lys17Asn	missense_variant	Exon 3 of 10	ENST00000292510.6	NP_057292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS28	ENST00000292510.6	c.51G>C	p.Lys17Asn	missense_variant	Exon 3 of 10	1	NM_016208.4	ENSP00000292510.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.51G>C (p.K17N) alteration is located in exon 3 (coding exon 2) of the VPS28 gene. This alteration results from a G to C substitution at nucleotide position 51, causing the lysine (K) at amino acid position 17 to be replaced by an asparagine (N). 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	0.63
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;T;.;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N;N;N;N;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;D;T;D;T;T;D
Sift4G	Benign	0.081	T;T;T;T;.;.;T
Polyphen		0.17	B;P;B;P;.;.;.
Vest4		0.50
MutPred		0.24		Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);Loss of methylation at K17 (P = 0.004);
MVP		0.27
MPC		0.21
ClinPred		0.66	D
GERP RS		5.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.79
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145651578;