8-99832368-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_152564.5(VPS13B):c.9331-1G>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 (★★). ClinVar reports functional evidence for this variant: "SCV001585869: 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).".

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 12)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS13B
NM_152564.5 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

Variant links:

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: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001585869: 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).

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. 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>A		splice_acceptor intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.9331-1G>A		splice_acceptor intron	N/A	NP_689777.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.9406-1G>A	splice_acceptor intron	N/A	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.9331-1G>A	splice_acceptor intron	N/A	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.9406-1G>A	splice_acceptor intron	N/A	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

70832

Hom.:

Cov.:

show subpopulations

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:

AN:

664258

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

327404

show subpopulations

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

African (AFR)

AF:

0.0000687

AC:

AN:

14556

American (AMR)

AF:

0.00

AC:

AN:

11254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11706

East Asian (EAS)

AF:

0.00

AC:

AN:

18694

South Asian (SAS)

AF:

0.00

AC:

AN:

29504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2054

European-Non Finnish (NFE)

AF:

0.00000377

AC:

AN:

530032

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000141

AC:

AN:

70832

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

33054

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

18708

American (AMR)

AF:

0.00

AC:

AN:

5954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1844

East Asian (EAS)

AF:

0.00

AC:

AN:

2224

South Asian (SAS)

AF:

0.00

AC:

AN:

1948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0000281

AC:

AN:

35556

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cohen syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.9

GERP RS

5.5

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over