Genetic Variant VPS45:p.Asp106Glu (chr1-150076261-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007259.5(VPS45):c.318C>G(p.Asp106Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D106D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VPS45
NM_007259.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.594

Publications

1 publications found

Variant links:

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

VPS45 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1331104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS45	NM_007259.5 link	c.318C>G	p.Asp106Glu	missense_variant	Exon 4 of 15	ENST00000644510.2	NP_009190.2	Q9NRW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS45	ENST00000644510.2 link	c.318C>G	p.Asp106Glu	missense_variant	Exon 4 of 15		NM_007259.5	ENSP00000495563.1		Q9NRW7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249636

AF XY:

0.00000740

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457118

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33230

American (AMR)

AF:

0.00

AC:

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39442

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109048

Other (OTH)

AF:

0.00

AC:

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.4

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

.;.;T;.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.86

D;T;.;.;D;T;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.13

T;T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

2.0

.;.;M;.;M;.;.

PhyloP100

-0.59

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

.;.;N;N;.;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.23

.;.;T;T;.;T;.

Sift4G

Benign

0.36

.;T;T;T;.;T;.

Polyphen

0.0030

.;.;B;.;B;.;.

Vest4

0.17, 0.17, 0.17

MutPred

0.51

.;.;Loss of ubiquitination at K104 (P = 0.0755);.;Loss of ubiquitination at K104 (P = 0.0755);Loss of ubiquitination at K104 (P = 0.0755);Loss of ubiquitination at K104 (P = 0.0755);

MVP

0.36

MPC

0.41

ClinPred

0.12

GERP RS

-6.1

Varity_R

0.10

gMVP

0.35

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over