8-99096433-G-T

Position:

• chr8-99096433-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152564.5(VPS13B):​c.412+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS13B NM_152564.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.82

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99096433-G-T is Pathogenic according to our data. Variant chr8-99096433-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99096433-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.412+1G>T		splice_donor_variant, intron_variant		ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.412+1G>T		splice_donor_variant, intron_variant		ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.412+1G>T		splice_donor_variant, intron_variant		1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.412+1G>T		splice_donor_variant, intron_variant		1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

Cohen syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The homozygous c.412+1G>T variant in VPS13B was identified in our study in one individual with growth delay, intellectual disability, and microcephaly. The c.412+1G>T variant in VPS13B has been previously reported in one individual with Cohen syndrome (PMID: 26539891). This variant has also been reported in ClinVar (Variation ID: 402219) and has been interpreted as likely pathogenic by the Lupski Lab of the Baylor College of Medicine. The affected individual previously reported (PMID: 26539891) and the patient identified by our study were homozygotes for the variant, which increases the likelihood that the c.412+1G>T variant is pathogenic. A different nucleotide change that also results in a splice donor variant at the same site, c.412+1G>A has been reported likely pathogenic in ClinVar (Variation ID: 371467), and the variant being assessed here, c.412+1G>T, is predicted by SpliceAI to have a similar effect on splicing. This variant was absent from large population studies. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PS1_Supporting, PM2_Supporting, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs1057517295; hg19: chr8-100108661;