rs879255237

Positions:

• chr1-150077763-C-A

Variant summary

Our verdict is Pathogenic. Variant got 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 (★★).

• 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:3
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 55906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS45	NM_007259.5	c.671C>A	p.Thr224Asn	missense_variant	7/15	ENST00000644510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS45	ENST00000644510.2	c.671C>A	p.Thr224Asn	missense_variant	7/15		NM_007259.5	P3

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital neutropenia-myelofibrosis-nephromegaly syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 04, 2013	- -

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;.;.;.
MutationTaster	Benign	1.0	D;D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255237; hg19: chr1-150049841;