rs6468694

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017890.5(VPS13B):c.10294G>A(p.Gly3432Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,614,062 control chromosomes in the GnomAD database, including 12,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. G3432E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 1118 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11566 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 1.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019465387).

BP6

Variant 8-99853608-G-A is Benign according to our data. Variant chr8-99853608-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99853608-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.10294G>A	p.Gly3432Arg	missense_variant	56/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.10219G>A	p.Gly3407Arg	missense_variant	56/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.10294G>A	p.Gly3432Arg	missense_variant	56/62	1	NM_017890.5		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.10219G>A	p.Gly3407Arg	missense_variant	56/62	1	NM_152564.5	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17990

AN:

152064

Hom.:

1119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.113

GnomAD3 exomes

AF:

0.123

AC:

31009

AN:

251454

Hom.:

2019

AF XY:

0.123

AC XY:

16672

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.117

Gnomad SAS exome

AF:

0.0971

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.124

AC:

180685

AN:

1461880

Hom.:

11566

Cov.:

AF XY:

0.123

AC XY:

89725

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.171

Gnomad4 EAS exome

AF:

0.101

Gnomad4 SAS exome

AF:

0.0982

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.122

GnomAD4 genome

AF:

0.118

AC:

17993

AN:

152182

Hom.:

1118

Cov.:

AF XY:

0.117

AC XY:

8678

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.112

Gnomad4 SAS

AF:

0.0873

Gnomad4 FIN

AF:

0.112

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.112

Alfa

AF:

0.130

Hom.:

3321

Bravo

AF:

0.122

TwinsUK

AF:

0.135

AC:

500

ALSPAC

AF:

0.124

AC:

477

ESP6500AA

AF:

0.108

AC:

474

ESP6500EA

AF:

0.126

AC:

1082

ExAC

AF:

0.123

AC:

14944

Asia WGS

AF:

0.110

AC:

382

AN:

3478

EpiCase

AF:

0.131

EpiControl

AF:

0.134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2020	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

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

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Benign

0.29

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.055

Sift

Benign

0.53

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0010

B;B

Vest4

0.12

MutPred

0.30

.;Loss of relative solvent accessibility (P = 0.0676);

MPC

0.15

ClinPred

0.00090

GERP RS

2.4

Varity_R

0.027

gMVP

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over