15-40899338-C-A

Variant names:

• chr15-40899338-C-A
• rs553162824
• NM_020857.3:c.520C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020857.3(VPS18):​c.520C>A​(p.Leu174Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. L174V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS18 NM_020857.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.40
• Publications: 0 publications found

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]

VPS18 Gene-Disease associations (from GenCC):

• leukodystrophy

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06308979).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020857.3. 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
	VPS18	NM_020857.3	MANE Select	c.520C>A	p.Leu174Ile	missense	Exon 4 of 5	NP_065908.1	Q9P253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS18	ENST00000220509.10	TSL:1 MANE Select	c.520C>A	p.Leu174Ile	missense	Exon 4 of 5	ENSP00000220509.5	Q9P253
	VPS18	ENST00000943645.1		c.544C>A	p.Leu182Ile	missense	Exon 4 of 5	ENSP00000613704.1
	VPS18	ENST00000882105.1		c.390+130C>A		intron	N/A	ENSP00000552164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111498

Other (OTH) AF: 0.00 AC: 0 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.41
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		5.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.094
MutPred		0.45		Loss of catalytic residue at L174 (P = 0.0489)
MVP		0.043
MPC		0.40
ClinPred		0.35	T
GERP RS		4.7
Varity_R		0.096
gMVP		0.092
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs553162824; hg19: chr15-41191536;