rs61753722

Positions:

chr8-99431657-C-T

Variant summary

Our verdict is Benign. Variant got -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:12

Conservation

PhyloP100: 7.00

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=0.006599039).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.3203C>T	p.Thr1068Ile	missense_variant	22/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.3203C>T	p.Thr1068Ile	missense_variant	22/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.3203C>T	p.Thr1068Ile	missense_variant	22/62	1	NM_017890.5		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.3203C>T	p.Thr1068Ile	missense_variant	22/62	1	NM_152564.5	P1	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

GnomAD3 exomes

AF:

0.0105

AC:

2621

AN:

249926

Hom.:

AF XY:

0.0122

AC XY:

1646

AN XY:

135236

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 SAS exome

AF:

0.0334

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

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00475

Gnomad4 ASJ exome

AF:

0.00943

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0343

Gnomad4 FIN exome

AF:

0.0137

Gnomad4 NFE exome

AF:

0.00804

Gnomad4 OTH exome

AF:

0.0105

GnomAD4 genome

AF:

0.00790

AC:

1203

AN:

152260

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00975

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0369

Gnomad4 FIN

AF:

0.0144

Gnomad4 NFE

AF:

0.00896

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00900

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	This variant is associated with the following publications: (PMID: 29758347) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	VPS13B: BS1, BS2 -

Cohen syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 02, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

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

MutationTaster

Benign

1.0

D;D;D

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

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