NM_016023.5:c.83-1delG

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• PP5: Variant 8-91071136-AG-A is Pathogenic according to our data. Variant chr8-91071136-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 3341105.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTUD6B	NM_016023.5	c.83-1delG		splice_acceptor_variant, intron_variant	Intron 1 of 6	ENST00000404789.8	NP_057107.4
OTUD6B	NM_001416022.1	c.83-1delG		splice_acceptor_variant, intron_variant	Intron 1 of 5		NP_001402951.1
OTUD6B	NM_001286745.3	c.-361-1delG		splice_acceptor_variant, intron_variant	Intron 1 of 7		NP_001273674.1
OTUD6B	XM_047421864.1	c.83-1delG		splice_acceptor_variant, intron_variant	Intron 1 of 3		XP_047277820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8	c.83-1delG		splice_acceptor_variant, intron_variant	Intron 1 of 6	1	NM_016023.5	ENSP00000384190.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies Pathogenic:1

Sep 24, 2024

Molecular Diagnostic Laboratory, Beijing Chigene Translational Medicine Research Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_016023.5(OTUD6B):c.83-1del variant is not recorded in any population databases and the classification was made based on the the ACMG/AMP 2015 guideline. A similar splice acceptor variant, c.83-2del, has been recorded Pathogenic in ClinVar, id RCV000488135.2 and RCV000491932.2. The patient had the characteristic features of the IDDFSDA syndrome, Intellectual disability, facial dysmorphism, epilepsy, distinctive face and overlapping toes, meeting the diagnostic criteria for the disorder. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-92083364;