rs587716374

Variant names:

• chr1-150081372-C-G
• rs587716374
• NM_007259.5:c.718C>G
• VPS45 p.Leu240Val

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007259.5(VPS45):​c.718C>G​(p.Leu240Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,607,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L240L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.79
• Publications: 0 publications found

Genes affected

VPS45 (HGNC:14579): (vacuolar protein sorting 45 homolog) 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 is a member of the Sec1 domain family, and shows a high degree of sequence similarity to mouse, rat and yeast Vps45. The exact function of this gene is not known, but its high expression in peripheral blood mononuclear cells suggests a role in trafficking proteins, including inflammatory mediators. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2013]

VPS45 Gene-Disease associations (from GenCC):

• congenital neutropenia-myelofibrosis-nephromegaly syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007259.5. 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
	VPS45	NM_007259.5	MANE Select	c.718C>G	p.Leu240Val	missense	Exon 8 of 15	NP_009190.2
	VPS45	NM_001279353.2		c.403C>G	p.Leu135Val	missense	Exon 6 of 14	NP_001266282.1	Q9NRW7-2
	VPS45	NM_001279354.2		c.610C>G	p.Leu204Val	missense	Exon 8 of 15	NP_001266283.1	A0A2R8YE10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS45	ENST00000644510.2	MANE Select	c.718C>G	p.Leu240Val	missense	Exon 8 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.718C>G	p.Leu240Val	missense	Exon 8 of 16	ENSP00000513813.1	A0A8V8TM00
	VPS45	ENST00000644526.2		c.718C>G	p.Leu240Val	missense	Exon 8 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244458 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1455268 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724064

African (AFR) AF: 0.00 AC: 0 AN: 32852

American (AMR) AF: 0.0000232 AC: 1 AN: 43112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39148

South Asian (SAS) AF: 0.00 AC: 0 AN: 84914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110016

Other (OTH) AF: 0.0000333 AC: 2 AN: 60080

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital neutropenia-myelofibrosis-nephromegaly syndrome (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.037	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.48
Mutation Taster		=37/63	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587716374;

hg19: chr1-150053454;