8-99832368-G-T

Position:

• chr8-99832368-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_017890.5(VPS13B):​c.9406-1G>T variant causes a splice acceptor change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.081 (0 hom., cov: 12)
  • Exomes 𝑓: 0.11 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS13B NM_017890.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 6.89

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.2, offset of 16, new splice context is: ttattattttcgtgttccAGaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 8-99832368-G-T is Pathogenic according to our data. Variant chr8-99832368-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56699.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4}. Variant chr8-99832368-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.9406-1G>T		splice_acceptor_variant		ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.9331-1G>T		splice_acceptor_variant		ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000357162.7	c.9331-1G>T		splice_acceptor_variant		1	NM_152564.5	ENSP00000349685	P1
VPS13B	ENST00000358544.7	c.9406-1G>T		splice_acceptor_variant		1	NM_017890.5	ENSP00000351346

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5468 AN: 67484 Hom.: 0 Cov.: 12 FAILED QC

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.0719

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.0231

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.0743

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.111 AC: 64728 AN: 583638 Hom.: 1 Cov.: 32 AF XY: 0.108 AC XY: 31009 AN XY: 288102

Gnomad4 AFR exome AF: 0.0959

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.0849

Gnomad4 EAS exome AF: 0.0511

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.0465

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.0945

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0810 AC: 5467 AN: 67510 Hom.: 0 Cov.: 12 AF XY: 0.0771 AC XY: 2437 AN XY: 31612

Gnomad4 AFR AF: 0.0873

Gnomad4 AMR AF: 0.0593

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.0846

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.0378

Gnomad4 NFE AF: 0.0856

Gnomad4 OTH AF: 0.0735

ExAC AF: 0.00426 AC: 340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2018	Variant summary: VPS13B c.9406-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Two predict the variant strengthens a cryptic 3 acceptor site in exon 52. These predictions were confirmed by at least one publication reporting experimental evidence that this variant affects mRNA splicing. Results showed that the variant lead to the deletion of 16 exonic bases and, thus, a frameshift in mRNA (Hennies 2004). The variant allele was not found in 57574 control chromosomes (gnomAD). c.9406-1G>T has been reported in the literature in multiple individuals affected with Cohen Syndrome in either homozygous or compound heterozygous state (Hennies 2004, Rauch 2006, Duplomb 2014) . These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a deficiency in Golgi N-glycosylation (Duplomb 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 15154116). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 56699). Disruption of this splice site has been observed in individuals with Cohen syndrome (PMID: 15154116, 19190672). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 51 of the VPS13B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2023

Observed in apparent homozygous state in patients with Cohen syndrome in the literature (Hennies 2004, Rauch 2006) and not observed in homozygous state in controls; Observed with another canonical splice variant in VPS13B, phase (cis or trans) unknown, in a patient with a personal history consistent with Cohen syndrome (El Chehadeh-Djebbar 2013); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25060287, 19190672, 15154116, 24334764, 16917849, 31825161, 31589614, 29618732, 23188044) -

VPS13B-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

The VPS13B c.9331-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported as causative for autosomal recessive Cohen syndrome (described as c.9406-1G>T, Hennies et al. 2004. PubMed ID: 15154116; described as IVS51-1G>T, El Chehadeh-Djebbar et al. 2012. PubMed ID: 23188044; Duplomb et al. 2013. PubMed ID: 24334764). Variants that disrupt the consensus splice acceptor site in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: 17
DS_AL_spliceai		0.73		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834119; hg19: chr8-100844596;