rs113671330

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.9424A>G(p.Ser3142Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 1,382,896 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. S3142N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 21)

Exomes 𝑓: 0.0077 ( 98 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.81

Publications

7 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=0.0035758317).

BP6

Variant 8-99832387-A-G is Benign according to our data. Variant chr8-99832387-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95874.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 = 0.00689 (694/100794) while in subpopulation SAS AF = 0.0257 (91/3534). AF 95% confidence interval is 0.0215. There are 6 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.9424A>G	p.Ser3142Gly	missense_variant	Exon 52 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 link	c.9349A>G	p.Ser3117Gly	missense_variant	Exon 52 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.9424A>G	p.Ser3142Gly	missense_variant	Exon 52 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7 link	c.9349A>G	p.Ser3117Gly	missense_variant	Exon 52 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes

AF:

0.00689

AC:

694

AN:

100764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00312

Gnomad ASJ

AF:

0.0255

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.0257

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.0274

Gnomad NFE

AF:

0.00841

Gnomad OTH

AF:

0.00972

GnomAD2 exomes

AF:

0.00931

AC:

1368

AN:

146868

AF XY:

0.0112

show subpopulations

Gnomad AFR exome

AF:

0.000783

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00782

Gnomad OTH exome

AF:

0.00942

GnomAD4 exome

AF:

0.00775

AC:

9931

AN:

1282102

Hom.:

Cov.:

AF XY:

0.00849

AC XY:

5369

AN XY:

632488

show subpopulations

African (AFR)

AF:

0.00172

AC:

AN:

27286

American (AMR)

AF:

0.00251

AC:

AN:

30248

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

451

AN:

21892

East Asian (EAS)

AF:

0.0000641

AC:

AN:

31202

South Asian (SAS)

AF:

0.0259

AC:

1930

AN:

74396

European-Finnish (FIN)

AF:

0.00380

AC:

154

AN:

40476

Middle Eastern (MID)

AF:

0.0320

AC:

133

AN:

4154

European-Non Finnish (NFE)

AF:

0.00668

AC:

6683

AN:

1001008

Other (OTH)

AF:

0.00885

AC:

455

AN:

51440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

460

920

1379

1839

2299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00689

AC:

694

AN:

100794

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

358

AN XY:

47128

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

24816

American (AMR)

AF:

0.00312

AC:

AN:

8344

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

AN:

2664

East Asian (EAS)

AF:

0.000279

AC:

AN:

3588

South Asian (SAS)

AF:

0.0257

AC:

AN:

3534

European-Finnish (FIN)

AF:

0.00641

AC:

AN:

4370

Middle Eastern (MID)

AF:

0.0303

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.00841

AC:

432

AN:

51346

Other (OTH)

AF:

0.00964

AC:

AN:

1348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

126

157

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:

0.00675

Hom.:

Bravo

AF:

0.00413

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00629

AC:

ExAC

AF:

0.00620

AC:

737

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16648375)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cohen syndrome

Benign:4

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 30, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:2

Jan 17, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 02, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Sep 22, 2017

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

Benign

0.067

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.0

.;L

PhyloP100

2.8

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.093

Sift

Benign

0.29

T;T

Sift4G

Benign

0.23

T;T

Vest4

0.28

ClinPred

0.023

GERP RS

4.4

Varity_R

0.16

gMVP

0.21

Mutation Taster

=99/1

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