rs759317757

Positions:

• chr8-91078415-AAACTT-A

Variant summary

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

The NM_016023.5(OTUD6B):​c.379_383del​(p.Leu127ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTUD6B NM_016023.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.72

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-91078415-AAACTT-A is Pathogenic according to our data. Variant chr8-91078415-AAACTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 375702.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.379_383del	p.Leu127ArgfsTer8	frameshift_variant	4/7	ENST00000404789.8	NP_057107.4
OTUD6B	NM_001286745.3	c.76_80del	p.Leu26ArgfsTer8	frameshift_variant	5/8		NP_001273674.1
OTUD6B	NM_001416022.1	c.298_302del	p.Leu100ArgfsTer8	frameshift_variant	3/6		NP_001402951.1
OTUD6B	XM_011517129.3	c.76_80del	p.Leu26ArgfsTer8	frameshift_variant	4/7		XP_011515431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8	c.379_383del	p.Leu127ArgfsTer8	frameshift_variant	4/7	1	NM_016023.5	ENSP00000384190

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444836 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 716914

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: 9.07e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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 observed in one family: 2 affected sibs were homozygous. 1 brother was 9yo, severe intellectual disability, epilepsy, IUGR, microcephalic, hypotonia, failure to thrive, cryptorchidism, dysmorphic features, broad thumbs. Second brother was 3yo, severe delays, epilepsy, IUGR, microcephaly, hypotonia, failure to thrive, cortical and white matter atrophy, sacral dimple, VSD, cryptorchidism, dysmorphic features. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 03, 2017

- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Apr 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs759317757; hg19: chr8-92090643;