rs386834119

Positions:

• chr8-99832368-G-A
• chr8-99832368-G-C
• chr8-99832368-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_017890.5(VPS13B):​c.9406-1G>A 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 Likely 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 20 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-99832368-G-A is Pathogenic according to our data. Variant chr8-99832368-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 70832 Hom.: 0 Cov.: 12 FAILED QC

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

Gnomad4 AFR exome AF: 0.0000687

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000377

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000281

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 21, 2023	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. 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 introduces a premature termination codon (PMID: 15154116, 19190672). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 20, 2022	PVS1, PM2, PM3 -

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
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		0.54		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

Publications

LitVar

Other links and lift over

dbSNP: rs386834119; hg19: chr8-100844596;