rs61753725

Positions:

chr8-99766875-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_017890.5(VPS13B):c.7227G>A(p.Pro2409=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,613,950 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0051 ( 28 hom. )

Consequence

VPS13B
NM_017890.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0180

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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 8-99766875-G-A is Benign according to our data. Variant chr8-99766875-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99766875-G-A is described in Lovd as [Benign]. Variant chr8-99766875-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.018 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.7227G>A	p.Pro2409=	synonymous_variant	40/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.7152G>A	p.Pro2384=	synonymous_variant	40/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.7227G>A	p.Pro2409=	synonymous_variant	40/62	1	NM_017890.5		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.7152G>A	p.Pro2384=	synonymous_variant	40/62	1	NM_152564.5	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

626

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00603

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00405

AC:

1016

AN:

251140

Hom.:

AF XY:

0.00414

AC XY:

562

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00569

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.00514

AC:

7510

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00507

AC XY:

3685

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00521

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000812

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.00580

Gnomad4 OTH exome

AF:

0.00591

GnomAD4 genome

AF:

0.00413

AC:

629

AN:

152234

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.00603

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00459

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	VPS13B: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2018	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

This alteration is classified as likely 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

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.5

DANN

Benign

0.62

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