8-99821393-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_152564.5(VPS13B):​c.9094G>T​(p.Asp3032Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000613 in 1,613,786 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: 𝑓 0.00072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

1
7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 6.70
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.048188686).
BP6
Variant 8-99821393-G-T is Benign according to our data. Variant chr8-99821393-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=7}. Variant chr8-99821393-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS13BNM_017890.5 linkc.9169G>T p.Asp3057Tyr missense_variant Exon 50 of 62 ENST00000358544.7 NP_060360.3 Q7Z7G8-1
VPS13BNM_152564.5 linkc.9094G>T p.Asp3032Tyr missense_variant Exon 50 of 62 ENST00000357162.7 NP_689777.3 Q7Z7G8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS13BENST00000358544.7 linkc.9169G>T p.Asp3057Tyr missense_variant Exon 50 of 62 1 NM_017890.5 ENSP00000351346.2 Q7Z7G8-1
VPS13BENST00000357162.7 linkc.9094G>T p.Asp3032Tyr missense_variant Exon 50 of 62 1 NM_152564.5 ENSP00000349685.2 Q7Z7G8-2

Frequencies

GnomAD3 genomes
AF:
0.000723
AC:
110
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00198
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00119
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000593
AC:
149
AN:
251098
Hom.:
1
AF XY:
0.000619
AC XY:
84
AN XY:
135678
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00166
Gnomad NFE exome
AF:
0.000934
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000601
AC:
879
AN:
1461642
Hom.:
0
Cov.:
31
AF XY:
0.000627
AC XY:
456
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00183
Gnomad4 NFE exome
AF:
0.000677
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.000723
AC:
110
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.000767
AC XY:
57
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00198
Gnomad4 NFE
AF:
0.00119
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000940
Hom.:
0
Bravo
AF:
0.000461
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000610
AC:
74
EpiCase
AF:
0.00109
EpiControl
AF:
0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cohen syndrome Uncertain:3Benign:2
Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 02, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 09, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

VPS13B NM_017890.4 exon 50 p.Asp3057Tyr (c.9169G>T): This variant has not been reported in the literature but is present in 0.2% (46/25108) of Finnish alleles and in 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-100833621-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar, with classifications ranging from benign to Uncertain significance (Variation ID:95873). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aug 07, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2Benign:2
Mar 07, 2013
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 07, 2019
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 14, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

VPS13B: BP4 -

not specified Uncertain:1
May 23, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Jul 08, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.9169G>T (p.D3057Y) alteration is located in exon 50 (coding exon 49) of the VPS13B gene. This alteration results from a G to T substitution at nucleotide position 9169, causing the aspartic acid (D) at amino acid position 3057 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

VPS13B-related disorder Benign:1
Feb 15, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.097
.;T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.048
T;T
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
0.63
.;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.8
N;N
REVEL
Uncertain
0.46
Sift
Benign
0.16
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.069
B;D
Vest4
0.54
MVP
0.70
MPC
0.55
ClinPred
0.088
T
GERP RS
5.7
Varity_R
0.27
gMVP
0.49

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: rs140095832; hg19: chr8-100833621; COSMIC: COSV62161645; API