chr1-150077763-C-A

Variant names:

• chr1-150077763-C-A
• rs879255237
• NM_007259.5:c.671C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007259.5(VPS45):​c.671C>A​(p.Thr224Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,236 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T224T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.56
• Publications: 7 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 1-150077763-C-A is Pathogenic according to our data. Variant chr1-150077763-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS45	NM_007259.5	c.671C>A	p.Thr224Asn	missense_variant	Exon 7 of 15	ENST00000644510.2	NP_009190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS45	ENST00000644510.2	c.671C>A	p.Thr224Asn	missense_variant	Exon 7 of 15		NM_007259.5	ENSP00000495563.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461236 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital neutropenia-myelofibrosis-nephromegaly syndrome Pathogenic:3

Jul 04, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 224 of the VPS45 protein (p.Thr224Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with severe congenital neutropenia (PMID: 23599270, 23738510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55906). 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 expected to disrupt VPS45 protein function. Experimental studies have shown that this missense change affects VPS45 function (PMID: 23599270). For these reasons, this variant has been classified as Pathogenic. -

Jun 19, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe congenital neutropenia Pathogenic:1

Apr 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VPS45 c.671C>A (p.Thr224Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251298 control chromosomes (gnomAD). c.671C>A has been observed in multiple individuals affected with Severe Congenital Neutropenia (e.g., Vilboux_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant reusults in reduced protein localization and altered cellular localization (Vilboux_2013). The following publication has been ascertained in the context of this evaluation (PMID: 23738510). ClinVar contains an entry for this variant (Variation ID: 55906). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.8	.;.;H;.;.;H;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	.;.;D;D;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	.;D;D;D;D;.;.;.;.
Polyphen		1.0	.;.;D;.;.;D;.;.;.
Vest4		0.96, 0.96
MutPred		0.93		.;.;Loss of catalytic residue at T224 (P = 0.0334);.;.;Loss of catalytic residue at T224 (P = 0.0334);.;Loss of catalytic residue at T224 (P = 0.0334);.;
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255237; hg19: chr1-150049841;