rs140601319

Positions:

chr8-99143090-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017890.5(VPS13B):c.1768G>A(p.Ala590Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,614,026 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 0.00089 ( 2 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:7

Conservation

PhyloP100: 4.35

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01972723).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS13B	NM_017890.5 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	13/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	13/62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	13/18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	13/62	1	NM_017890.5	ENSP00000351346		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.1768G>A	p.Ala590Thr	missense_variant	13/62	1	NM_152564.5	ENSP00000349685	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000836

AC:

210

AN:

251346

Hom.:

AF XY:

0.000824

AC XY:

112

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000886

AC:

1295

AN:

1461740

Hom.:

Cov.:

AF XY:

0.000858

AC XY:

624

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152286

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Sep 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	This variant is associated with the following publications: (PMID: 17990063, 19006247) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	VPS13B: BP4, BP5, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cohen syndrome

Uncertain:3Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 21, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2019

The p.A590T variant (also known as c.1768G>A), located in coding exon 12 of the VPS13B gene, results from a G to A substitution at nucleotide position 1768. The alanine at codon 590 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was determined to be paternally inherited in a 2 year old individual with clinically suspected Cohen syndrome; however, this individual was not found to carry a second VPS13B alteration (Katzaki E et al. J. Hum. Genet., 2007 Nov;52:1011-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

VPS13B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The VPS13B c.1768G>A variant is predicted to result in the amino acid substitution p.Ala590Thr. This variant was reported in the heterozygous state in an individual with clinical features of Cohen syndrome (Katzaki et al. 2007. PubMed ID: 17990063). Importantly, a second potentially pathogenic allele was not detected in this individual. This variant was also described as a variant of uncertain significance in a cohort of individuals with Cohen syndrome; however, in vitro functional data indicated that this variant may behave similar to wild type in regards to localization (Zorn et al. 2022. PubMed ID: 35690661). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent and found in two homozygotes in gnomAD. This frequency is higher than expected for a pathogenic variant. Although we suspect this variant may be benign, at this time its clinical significance is uncertain. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

.;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.19

T;T;T

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.94

P;P;P

Vest4

0.37

MVP

0.77

MPC

0.46

ClinPred

0.063

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.45

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