rs61753722

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017890.5(VPS13B):c.3203C>T(p.Thr1068Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,611,946 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1068P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0079 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 139 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.00

Publications

14 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006599039).

BP6

Variant 8-99431657-C-T is Benign according to our data. Variant chr8-99431657-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0079 (1203/152260) while in subpopulation SAS AF = 0.0369 (178/4826). AF 95% confidence interval is 0.0325. There are 11 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.3203C>T	p.Thr1068Ile	missense_variant	Exon 22 of 62	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 link	c.3203C>T	p.Thr1068Ile	missense_variant	Exon 22 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.3203C>T	p.Thr1068Ile	missense_variant	Exon 22 of 62	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 link	c.3203C>T	p.Thr1068Ile	missense_variant	Exon 22 of 62	1	NM_152564.5	ENSP00000349685.2		Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.00791

AC:

1204

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00976

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0373

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00894

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0105

AC:

2621

AN:

249926

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00910

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00948

AC:

13841

AN:

1459686

Hom.:

139

Cov.:

AF XY:

0.0103

AC XY:

7503

AN XY:

726188

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33438

American (AMR)

AF:

0.00475

AC:

212

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00943

AC:

246

AN:

26086

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39512

South Asian (SAS)

AF:

0.0343

AC:

2958

AN:

86114

European-Finnish (FIN)

AF:

0.0137

AC:

726

AN:

53128

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00804

AC:

8930

AN:

1110690

Other (OTH)

AF:

0.0105

AC:

632

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

622

1243

1865

2486

3108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00790

AC:

1203

AN:

152260

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41572

American (AMR)

AF:

0.00975

AC:

149

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0369

AC:

178

AN:

4826

European-Finnish (FIN)

AF:

0.0144

AC:

153

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00896

AC:

609

AN:

68000

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00854

Hom.:

Bravo

AF:

0.00650

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.0107

AC:

1298

Asia WGS

AF:

0.0130

AC:

AN:

3476

EpiCase

AF:

0.00955

EpiControl

AF:

0.00990

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 30, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29758347) -

Jan 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS13B: BS1, BS2 -

Cohen syndrome

Benign:4

Feb 03, 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:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

May 02, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 06, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.065

.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.8

L;L

PhyloP100

7.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.13

Sift

Benign

0.51

T;T

Sift4G

Uncertain

0.032

D;D

Polyphen

0.99

D;D

Vest4

0.86

MPC

0.42

ClinPred

0.022

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.68

Mutation Taster

=41/59

disease causing

(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