rs386834116

Positions:

• chr8-99819403-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_017890.5(VPS13B):​c.8697-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VPS13B NM_017890.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9865
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.240

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 8-99819403-A-G is Pathogenic according to our data. Variant chr8-99819403-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99819403-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.8697-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358544.7
VPS13B	NM_152564.5	c.8622-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.8622-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.8697-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250926 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461226 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2022	This variant has been observed in individual(s) with Cohen syndrome (PMID: 22855652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs386834116, gnomAD 0.003%). This sequence change falls in intron 47 of the VPS13B gene. It does not directly change the encoded amino acid sequence of the VPS13B protein. ClinVar contains an entry for this variant (Variation ID: 56697). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2023	Variant summary: VPS13B c.8697-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site eight nucleotides upstream into intron 47. Two predict the variant abolishes the canonical 3' acceptor site and one predicts the variant weakens the canonical 3' acceptor site. This impact on splicing was confirmed via cDNA sequencing by Athanasakis_2012. The variant allele was found at a frequency of 4e-06 in 250926 control chromosomes (gnomAD). c.8697-9A>G has been reported in the literature in at least one compound heterozygous individuals affected with Cohen Syndrome (Athanasakis_2012). These data do not allow any conclusion about variant significance. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2016

The c.8697-9A>G variant in the VPS13B gene has been reported previously in an individual with Cohen syndrome who harbored this variant in trans with another pathogenic variant (Athanasakis et al., 2012). The c.8697-9A>G variant creates a cryptic splice acceptor site 8 base pairs upstream of the canonical splice acceptor site in intron 47. In vitro studies demonstrated that this variant results in an abnormal message and is predicted to lead to nonsense-mediated mRNA decay if the message is used for protein translation (Athanasakis et al., 2012). The c.8697-9A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.8697-9A>G as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.99		Position offset: 9

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834116; hg19: chr8-100831631;