rs1064797102

Positions:

• chr8-91071136-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016023.5(OTUD6B):​c.83-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,459,624 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTUD6B NM_016023.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.77

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 8-91071136-A-G is Pathogenic according to our data. Variant chr8-91071136-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 375703.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD6B	NM_016023.5	c.83-2A>G		splice_acceptor_variant, intron_variant		ENST00000404789.8	NP_057107.4
OTUD6B	NM_001416022.1	c.83-2A>G		splice_acceptor_variant, intron_variant			NP_001402951.1
OTUD6B	NM_001286745.3	c.-361-2A>G		splice_acceptor_variant, intron_variant			NP_001273674.1
OTUD6B	XM_047421864.1	c.83-2A>G		splice_acceptor_variant, intron_variant			XP_047277820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8	c.83-2A>G		splice_acceptor_variant, intron_variant		1	NM_016023.5	ENSP00000384190.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459624 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726132

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy;C0432072:Dysmorphic features;C3714756:Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Baylor Genetics

Jan 09, 2017

This variant was found in one family, homozygous in 2 affected sibs: one sister is 5yo, severe intellectual disability, epilepsy, microcephaly, hypotonia, mild vetriculomegaly, hypoplastic corpus callosum, dysmorphisms, scoliosis, toe syndactyly. Other sister is 3yo, severe delays, epilepsy, microcephaly, hypotonia, complex CHD, dysmorphisms, toe syndactyly. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

LitVar

Other links and lift over

dbSNP: rs1064797102; hg19: chr8-92083364;