chr1-150081949-G-C

Variant names:

• chr1-150081949-G-C
• rs1315600520
• NM_007259.5:c.888G>C

Variant summary

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

The NM_007259.5(VPS45):​c.888G>C​(p.Lys296Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K296K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.21
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19884291).

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.888G>C	p.Lys296Asn	missense	Exon 9 of 15	NP_009190.2
	VPS45	NM_001279353.2		c.573G>C	p.Lys191Asn	missense	Exon 7 of 14	NP_001266282.1	Q9NRW7-2
	VPS45	NM_001279354.2		c.780G>C	p.Lys260Asn	missense	Exon 9 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.888G>C	p.Lys296Asn	missense	Exon 9 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.888G>C	p.Lys296Asn	missense	Exon 9 of 16	ENSP00000513813.1	A0A8V8TM00
	VPS45	ENST00000644526.2		c.888G>C	p.Lys296Asn	missense	Exon 9 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000280 AC: 7 AN: 250436 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461106 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726874

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000157 AC: 7 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111680

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.000524 AC: 8 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.071
Sift	Benign	0.16	T
Sift4G	Benign	0.095	T
Polyphen		0.11	B
Vest4		0.39
MutPred		0.48		Gain of ubiquitination at K297 (P = 0.034)
MVP		0.73
MPC		0.68
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.31
Mutation Taster		=67/33	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: rs1315600520; hg19: chr1-150054031;