NM_007259.5:c.-4C>T

Variant names:

• chr1-150067854-C-T
• rs200563209
• NM_007259.5:c.-4C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007259.5(VPS45):​c.-4C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,814 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: VPS45 NM_007259.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 1.52
• 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]

OTUD7B (HGNC:16683): (OTU deubiquitinase 7B) Enables Lys48-specific deubiquitinase activity and thiol-dependent deubiquitinase. Involved in several processes, including negative regulation of I-kappaB kinase/NF-kappaB signaling; negative regulation of macromolecule metabolic process; and protein deubiquitination. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285184 (HGNC:58766):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

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.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_009190.2
	VPS45	NM_007259.5	MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 15	NP_009190.2
	VPS45	NM_001279354.2		c.-132C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000644510.2	MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000513813.1	A0A8V8TM00

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000354 AC: 89 AN: 251148 AF XY: 0.000324

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: 0.00120

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.000257 AC XY: 187 AN XY: 727146

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000294 AC: 327 AN: 1111862

Other (OTH) AF: 0.000232 AC: 14 AN: 60388

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000168 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital neutropenia-myelofibrosis-nephromegaly syndrome (1)
-	1	-	not specified (1)
-	-	1	VPS45-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		1.5
PromoterAI		-0.41	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs200563209; hg19: chr1-150039911;