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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.9406-1G>T		splice_acceptor intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.9331-1G>T		splice_acceptor intron	N/A	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.9406-1G>T		splice_acceptor intron	N/A	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.9331-1G>T		splice_acceptor intron	N/A	ENSP00000349685.2
	VPS13B	ENST00000682153.1		n.9406-1G>T		splice_acceptor intron	N/A	ENSP00000507923.1

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Cohen syndrome (5)
1	-	-	not provided (1)
1	-	-	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;