X-155228416-G-T

Variant summary

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

The NM_003372.7(VBP1):c.318G>T(p.Leu106Phe) 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: VBP1 NM_003372.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.922

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.318G>T	p.Leu106Phe	missense_variant	4/6	ENST00000286428.7
VBP1	NM_001303543.1	c.426G>T	p.Leu142Phe	missense_variant	4/6
VBP1	NM_001303544.1	c.303G>T	p.Leu101Phe	missense_variant	5/7
VBP1	NM_001303545.1	c.207G>T	p.Leu69Phe	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VBP1	ENST00000286428.7	c.318G>T	p.Leu106Phe	missense_variant	4/6	1	NM_003372.7	P1
VBP1	ENST00000535916.5	c.303G>T	p.Leu101Phe	missense_variant	5/7	2
VBP1	ENST00000625964.2	c.303G>T	p.Leu101Phe	missense_variant	4/6	5
VBP1	ENST00000460509.1	n.191G>T		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: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.318G>T (p.L106F) alteration is located in exon 4 (coding exon 4) of the VBP1 gene. This alteration results from a G to T substitution at nucleotide position 318, causing the leucine (L) at amino acid position 106 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Benign	0.21
Sift	Benign	0.22	T;.;T
Sift4G	Benign	0.53	T;T;T
Vest4		0.46
MutPred		0.56		.;.;Gain of catalytic residue at L106 (P = 0.003);
MVP		0.59
MPC		1.9
ClinPred		0.97	D
GERP RS		0.043
gMVP		0.65

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: chrX-154456698;