1-150072183-T-G

Position:

• chr1-150072183-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.732

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 Benign. Variant got -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 id is 474244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150072183-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS45	NM_007259.5	c.246T>G	p.Ile82Met	missense_variant	3/15	ENST00000644510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS45	ENST00000644510.2	c.246T>G	p.Ile82Met	missense_variant	3/15		NM_007259.5	P3

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5149 AN: 152110 Hom.: 242 Cov.: 31

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

GnomAD3 exomes AF: 0.0103 AC: 2570 AN: 249012 Hom.: 112 AF XY: 0.00798 AC XY: 1074 AN XY: 134636

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 SAS exome AF: 0.000299

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.: 29 AF XY: 0.00477 AC XY: 3451 AN XY: 724236

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00987

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000422

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0339 AC: 5161 AN: 152228 Hom.: 243 Cov.: 31 AF XY: 0.0329 AC XY: 2450 AN XY: 74420

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.00829 Hom.: 85

Bravo AF: 0.0394

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.108 AC: 475

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.0126 AC: 1524

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Congenital neutropenia-myelofibrosis-nephromegaly syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.26	.;.;T;.;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.54	T;T;.;.;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	.;.;N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.19	.;.;N;N;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.082	.;.;T;D;.;D;.
Sift4G	Benign	0.080	.;T;T;T;.;T;.
Polyphen		0.16	.;.;B;.;B;.;.
Vest4		0.18, 0.30, 0.22
MPC		0.33
ClinPred		0.0068	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs62622370; hg19: chr1-150044250;