rs148944527

Variant names:

• chr1-150068662-G-A
• rs148944527
• NM_007259.5:c.126G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_007259.5(VPS45):​c.126G>A​(p.Ser42Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,610,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: VPS45 NM_007259.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.51
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-150068662-G-A is Benign according to our data. Variant chr1-150068662-G-A is described in ClinVar as Benign. ClinVar VariationId is 541276.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS45	NM_007259.5	MANE Select	c.126G>A	p.Ser42Ser	synonymous	Exon 2 of 15	NP_009190.2
	VPS45	NM_001279353.2		c.18G>A	p.Ser6Ser	synonymous	Exon 2 of 14	NP_001266282.1	Q9NRW7-2
	VPS45	NM_001279354.2		c.18G>A	p.Ser6Ser	synonymous	Exon 2 of 15	NP_001266283.1	A0A2R8YE10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS45	ENST00000644510.2	MANE Select	c.126G>A	p.Ser42Ser	synonymous	Exon 2 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.126G>A	p.Ser42Ser	synonymous	Exon 2 of 16	ENSP00000513813.1	A0A8V8TM00
	VPS45	ENST00000644526.2		c.126G>A	p.Ser42Ser	synonymous	Exon 2 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes AF: 0.000704 AC: 107 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000165 AC: 41 AN: 248930 AF XY: 0.000119

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000686 AC: 100 AN: 1458428 Hom.: 0 Cov.: 30 AF XY: 0.0000593 AC XY: 43 AN XY: 725432

African (AFR) AF: 0.00240 AC: 80 AN: 33300

American (AMR) AF: 0.000113 AC: 5 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110272

Other (OTH) AF: 0.000116 AC: 7 AN: 60240

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74400

African (AFR) AF: 0.00253 AC: 105 AN: 41486

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000797

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital neutropenia-myelofibrosis-nephromegaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148944527; hg19: chr1-150040719;