15-40896007-C-T

Variant names:

• chr15-40896007-C-T
• NM_020857.3:c.161C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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]

ACMG classification

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
VPS18	NM_020857.3	c.161C>T	p.Ser54Phe	missense_variant	Exon 2 of 5	ENST00000220509.10	NP_065908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS18	ENST00000220509.10	c.161C>T	p.Ser54Phe	missense_variant	Exon 2 of 5	1	NM_020857.3	ENSP00000220509.5
VPS18	ENST00000558474.1	c.161C>T	p.Ser54Phe	missense_variant	Exon 2 of 4	3		ENSP00000453555.1
VPS18	ENST00000558855.5	n.161C>T		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000453265.1

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

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;