11-65096282-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013265.4(VPS51):​c.32C>T​(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,519,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

VPS51
NM_013265.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.00600
Variant links:
Genes affected
VPS51 (HGNC:1172): (VPS51 subunit of GARP complex) This gene encodes a member of the vacuolar protein sorting-associated protein 51 family. The encoded protein is a component of the Golgi-associated retrograde protein complex which acts as a tethering factor for carriers in retrograde transport from the early and late endosomes to the trans-Golgi network. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0049692094).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS51NM_013265.4 linkc.32C>T p.Pro11Leu missense_variant Exon 1 of 10 ENST00000279281.8 NP_037397.2 Q9UID3-1
VPS51NR_073519.2 linkn.69C>T non_coding_transcript_exon_variant Exon 1 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS51ENST00000279281.8 linkc.32C>T p.Pro11Leu missense_variant Exon 1 of 10 1 NM_013265.4 ENSP00000279281.3 Q9UID3-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000136
AC:
15
AN:
110116
Hom.:
0
AF XY:
0.000129
AC XY:
8
AN XY:
61930
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000628
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000666
AC:
91
AN:
1367194
Hom.:
0
Cov.:
32
AF XY:
0.0000666
AC XY:
45
AN XY:
675426
show subpopulations
Gnomad4 AFR exome
AF:
0.000455
Gnomad4 AMR exome
AF:
0.000531
Gnomad4 ASJ exome
AF:
0.0000416
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000262
Gnomad4 FIN exome
AF:
0.0000213
Gnomad4 NFE exome
AF:
0.0000411
Gnomad4 OTH exome
AF:
0.000230
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000952
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 22, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.32C>T (p.P11L) alteration is located in exon 1 (coding exon 1) of the VPS51 gene. This alteration results from a C to T substitution at nucleotide position 32, causing the proline (P) at amino acid position 11 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pontocerebellar hypoplasia, type 13 Uncertain:1
Jun 11, 2024
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at position 32 of the coding sequence of the VPS51 gene that results in a proline to leucine amino acid change at residue 11 of the VPS51 subunit of GARP complex protein. This is a previously reported variant (ClinVar 2366203) that has not been observed in individuals affected by a VPS51-related disorder in the published literature, to our knowledge. This variant is present in 105 of 1519474 alleles (0.0069%) in the gnomAD v4.1.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Pro11 residue at this position is poorly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
9.7
DANN
Benign
0.82
DEOGEN2
Benign
0.0049
T;T;T;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.68
T;T;T;T;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.0050
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
.;.;L;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-0.090
N;N;N;N;.
REVEL
Benign
0.067
Sift
Benign
0.20
T;T;T;T;.
Sift4G
Benign
0.23
T;T;T;T;.
Polyphen
0.0
.;.;B;.;.
Vest4
0.12
MutPred
0.12
.;Loss of glycosylation at P11 (P = 0.0382);Loss of glycosylation at P11 (P = 0.0382);Loss of glycosylation at P11 (P = 0.0382);Loss of glycosylation at P11 (P = 0.0382);
MVP
0.055
MPC
0.70
ClinPred
0.058
T
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.022
gMVP
0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747134833; hg19: chr11-64863754; API