rs1315600520

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-150081949-G-A
• chr1-150081949-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_007259.5(VPS45):​c.888G>A​(p.Lys296Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS45 NM_007259.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-150081949-G-A is Benign according to our data. Variant chr1-150081949-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1336803.
• BP7: Synonymous conserved (PhyloP=3.21 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.888G>A	p.Lys296Lys	synonymous	Exon 9 of 15	NP_009190.2
	VPS45	NM_001279353.2		c.573G>A	p.Lys191Lys	synonymous	Exon 7 of 14	NP_001266282.1	Q9NRW7-2
	VPS45	NM_001279354.2		c.780G>A	p.Lys260Lys	synonymous	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>A	p.Lys296Lys	synonymous	Exon 9 of 15	ENSP00000495563.1	Q9NRW7-1
	VPS45	ENST00000698584.1		c.888G>A	p.Lys296Lys	synonymous	Exon 9 of 16	ENSP00000513813.1	A0A8V8TM00
	VPS45	ENST00000644526.2		c.888G>A	p.Lys296Lys	synonymous	Exon 9 of 16	ENSP00000494363.1	A0A2R8YD95

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		3.2
Mutation Taster		=93/7	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;