1-150072183-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007259.5(VPS45):c.246T>G(p.Ile82Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,608,100 control chromosomes in the GnomAD database, including 520 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I82I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.034 ( 243 hom., cov: 31)

Exomes 𝑓: 0.0051 ( 277 hom. )

Consequence

VPS45
NM_007259.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.732

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018512905).

BP6

Variant 1-150072183-T-G is Benign according to our data. Variant chr1-150072183-T-G is described in ClinVar as Benign. ClinVar VariationId is 474244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS45	NM_007259.5	MANE Select	c.246T>G	p.Ile82Met	missense	Exon 3 of 15	NP_009190.2
VPS45	NM_001279353.2		c.138T>G	p.Ile46Met	missense	Exon 3 of 14	NP_001266282.1	Q9NRW7-2
VPS45	NM_001279354.2		c.138T>G	p.Ile46Met	missense	Exon 3 of 15	NP_001266283.1	A0A2R8YE10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS45	ENST00000644510.2	MANE Select	c.246T>G	p.Ile82Met	missense	Exon 3 of 15	ENSP00000495563.1	Q9NRW7-1
VPS45	ENST00000698584.1		c.246T>G	p.Ile82Met	missense	Exon 3 of 16	ENSP00000513813.1	A0A8V8TM00
VPS45	ENST00000644526.2		c.246T>G	p.Ile82Met	missense	Exon 3 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5149

AN:

152110

Hom.:

242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0208

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0103

AC:

2570

AN:

249012

AF XY:

0.00798

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.00908

Gnomad ASJ exome

AF:

0.00986

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00893

GnomAD4 exome

AF:

0.00515

AC:

7497

AN:

1455872

Hom.:

277

Cov.:

AF XY:

0.00477

AC XY:

3451

AN XY:

724236

show subpopulations

African (AFR)

AF:

0.114

AC:

3776

AN:

33078

American (AMR)

AF:

0.00987

AC:

437

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

260

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39478

South Asian (SAS)

AF:

0.000422

AC:

AN:

85392

European-Finnish (FIN)

AF:

0.000170

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.0296

AC:

167

AN:

5636

European-Non Finnish (NFE)

AF:

0.00193

AC:

2136

AN:

1108908

Other (OTH)

AF:

0.0113

AC:

676

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

287

575

862

1150

1437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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

AF:

0.0339

AC:

5161

AN:

152228

Hom.:

243

Cov.:

AF XY:

0.0329

AC XY:

2450

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.110

AC:

4572

AN:

41504

American (AMR)

AF:

0.0207

AC:

317

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68020

Other (OTH)

AF:

0.0280

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

229

457

686

914

1143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0147

Hom.:

224

Bravo

AF:

0.0394

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.108

AC:

475

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.0126

AC:

1524

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital neutropenia-myelofibrosis-nephromegaly syndrome (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.26

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

PhyloP100

0.73

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.19

REVEL

Benign

0.13

Sift

Benign

0.082

Sift4G

Benign

0.080

Polyphen

0.16

Vest4

0.18

MPC

0.33

ClinPred

0.0068

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.065

gMVP

0.39

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over