rs61759485

chr8-99442576-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017890.5(VPS13B):c.3386A>G(p.Lys1129Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00487 in 1,614,004 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1129E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (25 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.76

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009524286).
• BP6: Variant 8-99442576-A-G is Benign according to our data. Variant chr8-99442576-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99442576-A-G is described in Lovd as [Likely_benign]. Variant chr8-99442576-A-G is described in Lovd as [Benign]. Variant chr8-99442576-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.3386A>G	p.Lys1129Arg	missense_variant	23/62	ENST00000358544.7
VPS13B	NM_152564.5	c.3386A>G	p.Lys1129Arg	missense_variant	23/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.3386A>G	p.Lys1129Arg	missense_variant	23/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.3386A>G	p.Lys1129Arg	missense_variant	23/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00464 AC: 1166 AN: 251224 Hom.: 5 AF XY: 0.00474 AC XY: 644 AN XY: 135764

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00492 AC: 7197 AN: 1461706 Hom.: 25 Cov.: 31 AF XY: 0.00487 AC XY: 3542 AN XY: 727158

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.00553

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.00441 AC: 671 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74476

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00557 Hom.: 2

Bravo AF: 0.00459

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00518 AC: 629

EpiCase AF: 0.00485

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 15, 2022	This variant has been reported in the literature in at least 3 individuals with retinal disease including 1 individual with Cohen syndrome (Seifert 2009 PMID:19006247, Tiwari 2016 PMID:27353947, Stone 2017 PMID:28559085). Of note, at least 1 publication notes that this variant is not likely to be disease causing. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (417/68028) including 1 homozygote (https://gnomad.broadinstitute.org/variant/8-99442576-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign or Likely Benign (Variation ID:95845). Evolutionary conservation for this variant is unclear; suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2016	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2022	Variant summary: VPS13B c.3386A>G (p.Lys1129Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251224 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 1.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13B causing Cohen Syndrome phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.3386A>G in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2013	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	VPS13B: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	This variant is associated with the following publications: (PMID: 19006247, 27353947, 28559085) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2018

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. -

VPS13B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

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	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;B
Vest4		0.33
MVP		0.28
MPC		0.099
ClinPred		0.041	T
GERP RS		3.3
Varity_R		0.069
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61759485; hg19: chr8-100454804;