rs368313959

Positions:

chr8-91078383-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_016023.5(OTUD6B):c.343C>T(p.Arg115Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000543 in 1,585,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

OTUD6B
NM_016023.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.903

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 8-91078383-C-T is Pathogenic according to our data. Variant chr8-91078383-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OTUD6B	NM_016023.5 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	4/7	ENST00000404789.8	NP_057107.4
OTUD6B	NM_001416022.1 linkuse as main transcript	c.262C>T	p.Arg88Ter	stop_gained	3/6		NP_001402951.1
OTUD6B	NM_001286745.3 linkuse as main transcript	c.40C>T	p.Arg14Ter	stop_gained	5/8		NP_001273674.1
OTUD6B	XM_011517129.3 linkuse as main transcript	c.40C>T	p.Arg14Ter	stop_gained	4/7		XP_011515431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	4/7	1	NM_016023.5	ENSP00000384190		Q8N6M0-1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.0000589

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000158

AC:

AN:

209016

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

111606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000934

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000388

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.000563

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1433048

Hom.:

Cov.:

AF XY:

0.0000465

AC XY:

AN XY:

709984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000989

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000210

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000372

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000911

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28343629, 32924626) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 15, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 375701). This premature translational stop signal has been observed in individual(s) with an intellectual disability syndrome that includes seizures and facial dysmorphism (PMID: 28343629). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs368313959, gnomAD 0.08%). This sequence change creates a premature translational stop signal (p.Arg145*) in the OTUD6B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTUD6B are known to be pathogenic (PMID: 28343629). -

Epilepsy;C0432072:Dysmorphic features;C3714756:Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 09, 2017

This nonsense variant has been observed in our laboratory homozygous in 4 probands: 20-year-old female with hemihypertrophy, intellectual disability, epilepsy, contractures, brachydactyly; 14-year-old male with IUGR, intellectual disability, SNHL, dystonia, epilepsy, dysmorphisms, short stature, microcephaly, contractures, scoliosis, hypogammaglobulinemia, brain abnormalities; 18-year-old female with hearing loss, epilepsy, dysmorphic features, microcephaly, failure to thrive, scoliosis, contractures, quadriplegia, hypothyroidism, intellectual disability, recurrent infections; 1-year-old female with developmental delays, hypotonia, dysmorphisms, microcephaly, congenital heart disease, unilateral retinoblastoma, reduced cerebral white matter, mild ventriculomegaly. One of these had a deceased sibling with similar features (not tested). An additional family was identified through research with 4 similarly affected sibs (2 deceased): 3 found to be homozygous, 1 not tested. Heterozygotes are expected to be asymptomatic carriers. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.433C>T (p.R145*) alteration, located in exon 4 (coding exon 4) of the OTUD6B gene, consists of a C to T substitution at nucleotide position 433. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 145. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (36/240398) total alleles studied. The highest observed frequency was 0.09% (29/30828) of Latino alleles. This variant has been reported in the homozygous state in multiple unrelated individuals with syndromic intellectual disability (Santiago-Sim, 2017; Sánchez-Soler, 2020; Romero-Ibarguengoitia, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.84

MutationTaster

Benign

1.0

A;A

Vest4

0.39

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over