rs36074608

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017890.5(VPS13B):c.9567T>C(p.Ser3189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,613,574 control chromosomes in the GnomAD database, including 28,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3189S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.16 ( 2527 hom., cov: 30)

Exomes 𝑓: 0.18 ( 26061 hom. )

Consequence

VPS13B
NM_017890.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.00200

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-99832530-T-C is Benign according to our data. Variant chr8-99832530-T-C is described in ClinVar as [Benign]. Clinvar id is 95875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99832530-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.002 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.329 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.9567T>C	p.Ser3189=	synonymous_variant	52/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.9492T>C	p.Ser3164=	synonymous_variant	52/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.9567T>C	p.Ser3189=	synonymous_variant	52/62	1	NM_017890.5		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.9492T>C	p.Ser3164=	synonymous_variant	52/62	1	NM_152564.5	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24757

AN:

151738

Hom.:

2524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0747

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.312

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.342

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.180

GnomAD3 exomes

AF:

0.205

AC:

51563

AN:

251080

Hom.:

6841

AF XY:

0.197

AC XY:

26777

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.0742

Gnomad AMR exome

AF:

0.400

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.353

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.180

AC:

263438

AN:

1461720

Hom.:

26061

Cov.:

AF XY:

0.179

AC XY:

130222

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0703

Gnomad4 AMR exome

AF:

0.388

Gnomad4 ASJ exome

AF:

0.132

Gnomad4 EAS exome

AF:

0.328

Gnomad4 SAS exome

AF:

0.155

Gnomad4 FIN exome

AF:

0.168

Gnomad4 NFE exome

AF:

0.174

Gnomad4 OTH exome

AF:

0.172

GnomAD4 genome

AF:

0.163

AC:

24768

AN:

151854

Hom.:

2527

Cov.:

AF XY:

0.168

AC XY:

12497

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.0749

Gnomad4 AMR

AF:

0.312

Gnomad4 ASJ

AF:

0.126

Gnomad4 EAS

AF:

0.342

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.170

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.154

Hom.:

927

Bravo

AF:

0.173

Asia WGS

AF:

0.242

AC:

841

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.173

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Benign:8

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:6

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)	Sep 10, 2015	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, 2 labs classify as benign in ClinVar -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

6.6

Dann

Benign

0.59

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