rs386834119

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-99832368-G-A
• chr8-99832368-G-C
• chr8-99832368-G-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>A 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 0.000014 (0 hom., cov: 12)
  • Exomes 𝑓: 0.0000045 (0 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:3
• 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 8.7, offset of 16, new splice context is: ttaatattttcgtgttccAGaca. 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-A is Pathogenic according to our data. Variant chr8-99832368-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 370547.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>A		splice_acceptor_variant, intron_variant	Intron 51 of 61	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.9331-1G>A		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>A		splice_acceptor_variant, intron_variant	Intron 51 of 61	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.9331-1G>A		splice_acceptor_variant, intron_variant	Intron 51 of 61	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 1 AN: 70832 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000281

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000452 AC: 3 AN: 664258 Hom.: 0 Cov.: 32 AF XY: 0.00000305 AC XY: 1 AN XY: 327404

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

African (AFR) AF: 0.0000687 AC: 1 AN: 14556

American (AMR) AF: 0.00 AC: 0 AN: 11254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11706

East Asian (EAS) AF: 0.00 AC: 0 AN: 18694

South Asian (SAS) AF: 0.00 AC: 0 AN: 29504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2054

European-Non Finnish (NFE) AF: 0.00000377 AC: 2 AN: 530032

Other (OTH) AF: 0.00 AC: 0 AN: 27902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00181427), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000141 AC: 1 AN: 70832 Hom.: 0 Cov.: 12 AF XY: 0.0000303 AC XY: 1 AN XY: 33054

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

African (AFR) AF: 0.00 AC: 0 AN: 18708

American (AMR) AF: 0.00 AC: 0 AN: 5954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1844

East Asian (EAS) AF: 0.00 AC: 0 AN: 2224

South Asian (SAS) AF: 0.00 AC: 0 AN: 1948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.0000281 AC: 1 AN: 35556

Other (OTH) AF: 0.00 AC: 0 AN: 928

⚠️ 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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:3

Jul 20, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3 -

Feb 26, 2016

Counsyl

Significance: Likely 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. -

Nov 18, 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: 370547). Studies have shown that disruption of this splice site results in a 16-bp deletion, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15154116, 19190672). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	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		0.54		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;