8-99821393-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_017890.5(VPS13B):c.9169G>T(p.Asp3057Tyr) 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_017890.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.70

Publications

6 publications found

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]

VPS13B Gene-Disease associations (from GenCC):

Cohen syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.9169G>T	p.Asp3057Tyr	missense_variant	Exon 50 of 62	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 link	c.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
VPS13B	ENST00000358544.7 link	c.9169G>T	p.Asp3057Tyr	missense_variant	Exon 50 of 62	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 link	c.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.:

Cov.:

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

GnomAD2 exomes

AF:

0.000593

AC:

149

AN:

251098

AF XY:

0.000619

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 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.:

Cov.:

AF XY:

0.000627

AC XY:

456

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.000157

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000677

AC:

753

AN:

1111846

Other (OTH)

AF:

0.000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000723

AC:

110

AN:

152144

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41442

American (AMR)

AF:

0.000262

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68028

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000895

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000610

AC:

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

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. -

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

- -

Aug 07, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13B: BP4 -

Mar 07, 2013

Eurofins Ntd Llc (ga)

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

- -

Jan 07, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.048

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.63

.;N

PhyloP100

6.7

PrimateAI

Benign

0.46

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

GERP RS

5.7

Varity_R

0.27

gMVP

0.49

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over