rs144659538

Variant names:

• chr1-150077221-A-C
• NM_007259.5:c.566A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-150077221-A-C
• chr1-150077221-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007259.5(VPS45):​c.566A>C​(p.Glu189Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E189G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS45 NM_007259.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS45	NM_007259.5	c.566A>C	p.Glu189Ala	missense_variant	Exon 6 of 15	ENST00000644510.2	NP_009190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS45	ENST00000644510.2	c.566A>C	p.Glu189Ala	missense_variant	Exon 6 of 15		NM_007259.5	ENSP00000495563.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D;.;D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	.;L;.;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.
REVEL	Uncertain	0.51
Sift	Benign	0.21	.;T;.;.;.;.
Sift4G	Benign	0.19	.;T;T;.;.;.
Polyphen		0.050	.;B;.;B;.;.
Vest4		0.84, 0.83
MutPred		0.54		.;Gain of MoRF binding (P = 0.0635);.;Gain of MoRF binding (P = 0.0635);.;Gain of MoRF binding (P = 0.0635);
MVP		0.73
MPC		0.64
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-150049299;