rs140601319

chr8-99143090-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong 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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01972723).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.1768G>A	p.Ala590Thr	missense_variant	13/62	ENST00000358544.7
VPS13B	NM_152564.5	c.1768G>A	p.Ala590Thr	missense_variant	13/62	ENST00000357162.7
VPS13B	NM_015243.3	c.1768G>A	p.Ala590Thr	missense_variant	13/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.1768G>A	p.Ala590Thr	missense_variant	13/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.1768G>A	p.Ala590Thr	missense_variant	13/62	1	NM_152564.5	P1

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

GnomAD3 exomes AF: 0.000836 AC: 210 AN: 251346 Hom.: 2 AF XY: 0.000824 AC XY: 112 AN XY: 135844

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 SAS exome AF: 0.000457

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

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000762

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

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00122 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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	This variant is associated with the following publications: (PMID: 17990063, 19006247) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	VPS13B: BP4, BP5, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Sep 28, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cohen syndrome Uncertain:3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 23, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 21, 2015

- -

VPS13B-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2019

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. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

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
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
MutationTaster	Benign	1.0	D;D;D;D
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

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

Other links and lift over

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