rs140601319

Variant names:

• chr8-99143090-G-A
• rs140601319
• NM_017890.5:c.1768G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017890.5(VPS13B):​c.1768G>A​(p.Ala590Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,614,026 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. A590V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:7
• Conservation: PhyloP100: 4.35
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01972723).
• BP6: Variant 8-99143090-G-A is Benign according to our data. Variant chr8-99143090-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194256.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.1768G>A	p.Ala590Thr	missense_variant	Exon 13 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.1768G>A	p.Ala590Thr	missense_variant	Exon 13 of 62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3	c.1768G>A	p.Ala590Thr	missense_variant	Exon 13 of 18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.1768G>A	p.Ala590Thr	missense_variant	Exon 13 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.1768G>A	p.Ala590Thr	missense_variant	Exon 13 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000836 AC: 210 AN: 251346 AF XY: 0.000824

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000886 AC: 1295 AN: 1461740 Hom.: 2 Cov.: 31 AF XY: 0.000858 AC XY: 624 AN XY: 727166

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86254

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.00104 AC: 1155 AN: 1111940

Other (OTH) AF: 0.000762 AC: 46 AN: 60386

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74462

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.000588 AC: 9 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68022

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.000597

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4

Oct 17, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17990063, 19006247) -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 28, 2020

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS13B: BP4, BP5, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 27, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cohen syndrome Uncertain:3 Benign:3

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:1

Apr 21, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 12, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A590T variant (also known as c.1768G>A), located in coding exon 12 of the VPS13B gene, results from a G to A substitution at nucleotide position 1768. The alanine at codon 590 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was determined to be paternally inherited in a 2 year old individual with clinically suspected Cohen syndrome; however, this individual was not found to carry a second VPS13B alteration (Katzaki E et al. J. Hum. Genet., 2007 Nov;52:1011-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

VPS13B-related disorder Uncertain:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS13B c.1768G>A variant is predicted to result in the amino acid substitution p.Ala590Thr. This variant was reported in the heterozygous state in an individual with clinical features of Cohen syndrome (Katzaki et al. 2007. PubMed ID: 17990063). Importantly, a second potentially pathogenic allele was not detected in this individual. This variant was also described as a variant of uncertain significance in a cohort of individuals with Cohen syndrome; however, in vitro functional data indicated that this variant may behave similar to wild type in regards to localization (Zorn et al. 2022. PubMed ID: 35690661). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent and found in two homozygotes in gnomAD. This frequency is higher than expected for a pathogenic variant. Although we suspect this variant may be benign, at this time its clinical significance is uncertain. -

Intellectual disability Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		4.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;T;T
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.94	P;P;P
Vest4		0.37
MVP		0.77
MPC		0.46
ClinPred		0.063	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.45
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs140601319; hg19: chr8-100155318; COSMIC: COSV62022429;