1-150077221-A-G

Variant names:

• chr1-150077221-A-G
• rs144659538
• NM_007259.5:c.566A>G

Variant summary

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

The NM_007259.5(VPS45):​c.566A>G​(p.Glu189Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.06
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS45	NM_007259.5	MANE Select	c.566A>G	p.Glu189Gly	missense	Exon 6 of 15	NP_009190.2
	VPS45	NM_001279354.2		c.458A>G	p.Glu153Gly	missense	Exon 6 of 15	NP_001266283.1
	VPS45	NM_001279353.2		c.262-448A>G		intron	N/A	NP_001266282.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS45	ENST00000644510.2	MANE Select	c.566A>G	p.Glu189Gly	missense	Exon 6 of 15	ENSP00000495563.1
	VPS45	ENST00000698584.1		c.566A>G	p.Glu189Gly	missense	Exon 6 of 16	ENSP00000513813.1
	VPS45	ENST00000644526.2		c.566A>G	p.Glu189Gly	missense	Exon 6 of 16	ENSP00000494363.1

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000549 AC: 137 AN: 249710 AF XY: 0.000630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000955

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000672 AC: 982 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.000675 AC XY: 491 AN XY: 726982

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.000381 AC: 17 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86120

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000797 AC: 886 AN: 1111846

Other (OTH) AF: 0.000696 AC: 42 AN: 60364

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152312 Hom.: 0 Cov.: 31 AF XY: 0.000510 AC XY: 38 AN XY: 74472

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000686 Hom.: 1

Bravo AF: 0.000616

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000560 AC: 68

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital neutropenia-myelofibrosis-nephromegaly syndrome Uncertain:4

Jun 25, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 189 of the VPS45 protein (p.Glu189Gly). This variant is present in population databases (rs144659538, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VPS45-related conditions. ClinVar contains an entry for this variant (Variation ID: 541273). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS45 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 12, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS45 NM_007259.4 exon 6 p.Glu189Gly (c.566A>G): This variant has not been reported in the literature but is present in 0.1% (82/68028) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-150077221-A-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:541273). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. Of note, although this variant occurs in the exon, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Oct 23, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

not provided Uncertain:1

Jan 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1_stand-alone

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.68
Sift	Benign	0.12	T
Sift4G	Benign	0.079	T
Polyphen		0.45	B
Vest4		0.86
MVP		0.78
MPC		1.1
ClinPred		0.13	T
GERP RS		6.1
Varity_R		0.25
gMVP		0.54
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 0

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

Other links and lift over

dbSNP: rs144659538; hg19: chr1-150049299;