rs147342579

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_152564.5(VPS13B):ā€‹c.4757A>Gā€‹(p.Asn1586Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š‘“ 0.00032 ( 0 hom., cov: 32)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

3
6
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 9.02
Variant links:
Genes affected
VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27088195).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS13BNM_017890.5 linkuse as main transcriptc.4832A>G p.Asn1611Ser missense_variant 31/62 ENST00000358544.7 NP_060360.3 Q7Z7G8-1
VPS13BNM_152564.5 linkuse as main transcriptc.4757A>G p.Asn1586Ser missense_variant 31/62 ENST00000357162.7 NP_689777.3 Q7Z7G8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS13BENST00000358544.7 linkuse as main transcriptc.4832A>G p.Asn1611Ser missense_variant 31/621 NM_017890.5 ENSP00000351346.2 Q7Z7G8-1
VPS13BENST00000357162.7 linkuse as main transcriptc.4757A>G p.Asn1586Ser missense_variant 31/621 NM_152564.5 ENSP00000349685.2 Q7Z7G8-2

Frequencies

GnomAD3 genomes
AF:
0.000322
AC:
49
AN:
152076
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00116
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000840
AC:
21
AN:
249912
Hom.:
0
AF XY:
0.0000666
AC XY:
9
AN XY:
135144
show subpopulations
Gnomad AFR exome
AF:
0.00124
Gnomad AMR exome
AF:
0.0000291
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1460542
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
726598
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000322
AC:
49
AN:
152076
Hom.:
0
Cov.:
32
AF XY:
0.000310
AC XY:
23
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.00116
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000136
Hom.:
0
Bravo
AF:
0.000344
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000132
AC:
16

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 03, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 16, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsOct 05, 2017- -
Cohen syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2024- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 29, 2019- -
VPS13B-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 22, 2024The VPS13B c.4757A>G variant is predicted to result in the amino acid substitution p.Asn1586Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
1.9
.;M
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.30
Sift
Benign
0.13
T;T
Sift4G
Uncertain
0.029
D;D
Polyphen
0.99
D;D
Vest4
0.68
MVP
0.86
MPC
0.46
ClinPred
0.12
T
GERP RS
5.7
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.19
gMVP
0.33

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: rs147342579; hg19: chr8-100568689; API