15-40896007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020857.3(VPS18):​c.161C>T​(p.Ser54Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

VPS18
NM_020857.3 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67
Variant links:
Genes affected
VPS18 (HGNC:15972): (VPS18 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps18 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34320217).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS18NM_020857.3 linkc.161C>T p.Ser54Phe missense_variant Exon 2 of 5 ENST00000220509.10 NP_065908.1 Q9P253A0A024R9R3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS18ENST00000220509.10 linkc.161C>T p.Ser54Phe missense_variant Exon 2 of 5 1 NM_020857.3 ENSP00000220509.5 Q9P253
VPS18ENST00000558474.1 linkc.161C>T p.Ser54Phe missense_variant Exon 2 of 4 3 ENSP00000453555.1 H0YMC9
VPS18ENST00000558855.5 linkn.161C>T non_coding_transcript_exon_variant Exon 2 of 5 5 ENSP00000453265.1 H0YLM6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 08, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.161C>T (p.S54F) alteration is located in exon 2 (coding exon 2) of the VPS18 gene. This alteration results from a C to T substitution at nucleotide position 161, causing the serine (S) at amino acid position 54 to be replaced by a phenylalanine (F). 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
Benign
0.27
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Benign
0.21
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
0.94
P;.
Vest4
0.41
MutPred
0.50
Loss of disorder (P = 0.0239);Loss of disorder (P = 0.0239);
MVP
0.10
MPC
0.87
ClinPred
0.95
D
GERP RS
5.0
Varity_R
0.44
gMVP
0.25

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41188205; API