X-155228429-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003372.7(VBP1):c.331C>A(p.Leu111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: VBP1 NM_003372.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.17

Genes affected

VBP1 (HGNC:12662): (VHL binding protein 1) The protein encoded by this gene interacts with the Von Hippel-Lindau protein to form an intracellular complex. The encoded protein functions as a chaperone protein, and may play a role in the transport of the Von Hippel-Lindau protein from the perinuclear granules to the nucleus or cytoplasm. Alternative splicing and the use of alternate transcription start sites results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VBP1	NM_003372.7	c.331C>A	p.Leu111Met	missense_variant	4/6	ENST00000286428.7
VBP1	NM_001303543.1	c.439C>A	p.Leu147Met	missense_variant	4/6
VBP1	NM_001303544.1	c.316C>A	p.Leu106Met	missense_variant	5/7
VBP1	NM_001303545.1	c.220C>A	p.Leu74Met	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VBP1	ENST00000286428.7	c.331C>A	p.Leu111Met	missense_variant	4/6	1	NM_003372.7	P1
VBP1	ENST00000535916.5	c.316C>A	p.Leu106Met	missense_variant	5/7	2
VBP1	ENST00000625964.2	c.316C>A	p.Leu106Met	missense_variant	4/6	5
VBP1	ENST00000460509.1	n.204C>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Ependymoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

McDonnell Genome Institute, Washington University in St. Louis

Dec 29, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;.
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.013	D;D;D
Vest4		0.46
MutPred		0.76		.;.;Gain of catalytic residue at L111 (P = 3e-04);
MVP		0.71
MPC		1.8
ClinPred		0.95	D
GERP RS		1.3
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1000821034; hg19: chrX-154456711;