rs782269909

Variant names:

• chr1-150081366-G-A
• rs782269909
• NM_007259.5:c.712G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_007259.5(VPS45):​c.712G>A​(p.Glu238Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,605,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002290553: Experimental studies have shown that this missense change affects VPS45 function (PMID:23738510).". Synonymous variant affecting the same amino acid position (i.e. E238E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.97
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002290553: Experimental studies have shown that this missense change affects VPS45 function (PMID: 23738510).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-150081366-G-A is Pathogenic according to our data. Variant chr1-150081366-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.712G>A	p.Glu238Lys	missense	Exon 8 of 15	NP_009190.2
	VPS45	NM_001279353.2		c.397G>A	p.Glu133Lys	missense	Exon 6 of 14	NP_001266282.1	Q9NRW7-2
	VPS45	NM_001279354.2		c.604G>A	p.Glu202Lys	missense	Exon 8 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.712G>A	p.Glu238Lys	missense	Exon 8 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.712G>A	p.Glu238Lys	missense	Exon 8 of 16	ENSP00000513813.1	A0A8V8TM00
	VPS45	ENST00000644526.2		c.712G>A	p.Glu238Lys	missense	Exon 8 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000823 AC: 2 AN: 243062 AF XY: 0.0000152

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: 0.0000930

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453946 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 723432

African (AFR) AF: 0.00 AC: 0 AN: 32706

American (AMR) AF: 0.00 AC: 0 AN: 42936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 38974

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84734

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109474

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41254

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Congenital neutropenia-myelofibrosis-nephromegaly syndrome (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		Gain of methylation at E238 (P = 0.0242)
MVP		0.95
MPC		1.1
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.76
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782269909; hg19: chr1-150053448;