rs192850081

chr1-150076223-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007259.5(VPS45):c.290-10T>C variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00108 in 1,597,314 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: VPS45 NM_007259.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002111
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.67

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-150076223-T-C is Benign according to our data. Variant chr1-150076223-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS45	NM_007259.5	c.290-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS45	ENST00000644510.2	c.290-10T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_007259.5	P3

Frequencies

GnomAD3 genomes AF: 0.000884 AC: 134 AN: 151610 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00250

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00139 AC: 339 AN: 244296 Hom.: 2 AF XY: 0.00164 AC XY: 217 AN XY: 132528

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00351

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.00110 AC: 1594 AN: 1445588 Hom.: 6 Cov.: 29 AF XY: 0.00121 AC XY: 871 AN XY: 719512

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00329

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000988

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.000877 AC: 133 AN: 151726 Hom.: 0 Cov.: 30 AF XY: 0.00101 AC XY: 75 AN XY: 74126

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00230

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.00104

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Congenital neutropenia-myelofibrosis-nephromegaly syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.6
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs192850081; hg19: chr1-150048301;