8-99832368-G-T

Variant names:

• chr8-99832368-G-T
• rs386834119
• NM_017890.5:c.9406-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017890.5(VPS13B):​c.9406-1G>T variant causes a splice acceptor, intron 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 Pathogenic (★★).

• 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.89
• Publications: 4 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: Pathogenic. The variant received 16 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 Pathogenic. ClinVar VariationId is 56699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.9406-1G>T		splice_acceptor_variant, intron_variant	Intron 51 of 61	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.9331-1G>T		splice_acceptor_variant, intron_variant	Intron 51 of 61	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.9406-1G>T		splice_acceptor_variant, intron_variant	Intron 51 of 61	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.9331-1G>T		splice_acceptor_variant, intron_variant	Intron 51 of 61	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0810 AC: 5468 AN: 67484 Hom.: 0 Cov.: 12

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0959 AC: 1243 AN: 12956

American (AMR) AF: 0.149 AC: 1500 AN: 10096

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 902 AN: 10624

East Asian (EAS) AF: 0.0511 AC: 901 AN: 17634

South Asian (SAS) AF: 0.153 AC: 3716 AN: 24362

European-Finnish (FIN) AF: 0.0465 AC: 813 AN: 17484

Middle Eastern (MID) AF: 0.0943 AC: 175 AN: 1856

European-Non Finnish (NFE) AF: 0.115 AC: 53126 AN: 463736

Other (OTH) AF: 0.0945 AC: 2352 AN: 24890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0873 AC: 1560 AN: 17864

American (AMR) AF: 0.0593 AC: 341 AN: 5752

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 144 AN: 1760

East Asian (EAS) AF: 0.0846 AC: 179 AN: 2116

South Asian (SAS) AF: 0.0714 AC: 134 AN: 1876

European-Finnish (FIN) AF: 0.0378 AC: 114 AN: 3012

Middle Eastern (MID) AF: 0.0254 AC: 3 AN: 118

European-Non Finnish (NFE) AF: 0.0856 AC: 2880 AN: 33656

Other (OTH) AF: 0.0735 AC: 67 AN: 912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00426 AC: 340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:5

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cohen syndrome (PMID: 15154116, 19190672). ClinVar contains an entry for this variant (Variation ID: 56699). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15154116). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1

May 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		6.9
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386834119; hg19: chr8-100844596;