8-91071136-AG-A

Variant names:

• chr8-91071136-AG-A
• NM_016023.5:c.83-1delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016023.5(OTUD6B):​c.83-1delG variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTUD6B NM_016023.5 splice_acceptor, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.24
• Publications: 1 publications found

Genes affected

OTUD6B (HGNC:24281): (OTU deubiquitinase 6B) This gene encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Deubiquitinating enzymes are primarily involved in removing ubiquitin from proteins targeted for degradation. This protein may function as a negative regulator of the cell cycle in B cells. [provided by RefSeq, Nov 2013]

OTUD6B Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 10, new splice context is: ggcttttcaccaaaattcAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-91071136-AG-A is Pathogenic according to our data. Variant chr8-91071136-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3341105.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016023.5. 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
	OTUD6B	NM_016023.5	MANE Select	c.83-1delG		splice_acceptor intron	N/A	NP_057107.4
	OTUD6B	NM_001416022.1		c.83-1delG		splice_acceptor intron	N/A	NP_001402951.1
	OTUD6B	NM_001286745.3		c.-361-1delG		splice_acceptor intron	N/A	NP_001273674.1	Q8N6M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD6B	ENST00000404789.8	TSL:1 MANE Select	c.83-1delG		splice_acceptor intron	N/A	ENSP00000384190.4	Q8N6M0-1
	OTUD6B	ENST00000285420.8	TSL:1	c.173-1delG		splice_acceptor intron	N/A	ENSP00000285420.4	A0A087X0W9
	OTUD6B	ENST00000617869.4	TSL:1	c.173-1delG		splice_acceptor intron	N/A	ENSP00000483706.1	A0A087X0W9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: 13
DS_AL_spliceai		1.0		Position offset: 2

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

Other links and lift over

hg19: chr8-92083364;