chr15-40904186-G-A

Variant names:

• chr15-40904186-G-A
• rs8036080
• NM_020857.3:c.*845G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_020857.3(VPS18):​c.*845G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 152,262 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.019 (50 hom., cov: 32)
• Consequence: VPS18 NM_020857.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 8 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0188 (2865/152262) while in subpopulation NFE AF = 0.0293 (1995/67994). AF 95% confidence interval is 0.0283. There are 50 homozygotes in GnomAd4. There are 1352 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS18	NM_020857.3	c.*845G>A		downstream_gene_variant		ENST00000220509.10	NP_065908.1
VPS18	XM_011521843.3	c.*845G>A		downstream_gene_variant			XP_011520145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS18	ENST00000220509.10	c.*845G>A		downstream_gene_variant		1	NM_020857.3	ENSP00000220509.5

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2866 AN: 152144 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0129

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0188 AC: 2865 AN: 152262 Hom.: 50 Cov.: 32 AF XY: 0.0182 AC XY: 1352 AN XY: 74460

African (AFR) AF: 0.00404 AC: 168 AN: 41554

American (AMR) AF: 0.0125 AC: 191 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4818

European-Finnish (FIN) AF: 0.0372 AC: 395 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0293 AC: 1995 AN: 67994

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0242 Hom.: 161

Bravo AF: 0.0161

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.74
PhyloP100		1.8

Splicing

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

Other links and lift over

dbSNP: rs8036080; hg19: chr15-41196384;