chr8-99848882-C-T

Position:

chr8-99848882-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017890.5(VPS13B):c.10124C>T(p.Thr3375Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,934 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 66 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.02

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004468918).

BP6

Variant 8-99848882-C-T is Benign according to our data. Variant chr8-99848882-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99848882-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.10124C>T	p.Thr3375Ile	missense_variant	55/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 linkuse as main transcript	c.10049C>T	p.Thr3350Ile	missense_variant	55/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.10124C>T	p.Thr3375Ile	missense_variant	55/62	1	NM_017890.5	ENSP00000351346		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.10049C>T	p.Thr3350Ile	missense_variant	55/62	1	NM_152564.5	ENSP00000349685	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1013

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00973

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00965

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00801

AC:

2015

AN:

251428

Hom.:

AF XY:

0.00882

AC XY:

1199

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00708

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.00959

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.00875

AC:

12785

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

6558

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00704

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0113

Gnomad4 FIN exome

AF:

0.00348

Gnomad4 NFE exome

AF:

0.00922

Gnomad4 OTH exome

AF:

0.00863

GnomAD4 genome

AF:

0.00663

AC:

1010

AN:

152322

Hom.:

Cov.:

AF XY:

0.00667

AC XY:

497

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00811

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00973

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00966

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00924

Hom.:

Bravo

AF:

0.00672

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0112

AC:

ExAC

AF:

0.00810

AC:

984

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0122

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VPS13B: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2019	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cohen syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 17, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

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

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.43

DANN

Benign

0.85

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.099

Sift

Benign

0.21

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0010

B;B

Vest4

0.17

MVP

0.60

MPC

0.13

ClinPred

0.0038

GERP RS

3.9

Varity_R

0.043

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