chr8-99135729-A-G

Position:

chr8-99135729-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The ENST00000357162.7(VPS13B):c.1559A>G(p.His520Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,613,188 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H520D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 2 hom. )

Consequence

VPS13B
ENST00000357162.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 8.65

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 Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP6

Variant 8-99135729-A-G is Benign according to our data. Variant chr8-99135729-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193906.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}. Variant chr8-99135729-A-G is described in Lovd as [Likely_benign].

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.1559A>G	p.His520Arg	missense_variant	11/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 linkuse as main transcript	c.1559A>G	p.His520Arg	missense_variant	11/62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3 linkuse as main transcript	c.1559A>G	p.His520Arg	missense_variant	11/18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.1559A>G	p.His520Arg	missense_variant	11/62	1	NM_017890.5	ENSP00000351346		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.1559A>G	p.His520Arg	missense_variant	11/62	1	NM_152564.5	ENSP00000349685	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000810

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000613

AC:

154

AN:

251028

Hom.:

AF XY:

0.000582

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000613

AC:

895

AN:

1460970

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

428

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000678

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152218

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000810

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000806

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cohen syndrome

Uncertain:4Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 01, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 10, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2020

The p.H520R variant (also known as c.1559A>G), located in coding exon 10 of the VPS13B gene, results from an A to G substitution at nucleotide position 1559. The histidine at codon 520 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

VPS13B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.9

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.84

MVP

0.95

MPC

0.35

ClinPred

0.13

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.40

Position offset: -1

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