NM_016023.5:c.343C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_016023.5(OTUD6B):c.343C>T(p.Arg115*) 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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

OTUD6B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 8-91078383-C-T is Pathogenic according to our data. Variant chr8-91078383-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
OTUD6B	NM_016023.5 link	c.343C>T	p.Arg115*	stop_gained	Exon 4 of 7	ENST00000404789.8	NP_057107.4
OTUD6B	NM_001416022.1 link	c.262C>T	p.Arg88*	stop_gained	Exon 3 of 6		NP_001402951.1
OTUD6B	NM_001286745.3 link	c.40C>T	p.Arg14*	stop_gained	Exon 5 of 8		NP_001273674.1
OTUD6B	XM_011517129.3 link	c.40C>T	p.Arg14*	stop_gained	Exon 4 of 7		XP_011515431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8 link	c.343C>T	p.Arg115*	stop_gained	Exon 4 of 7	1	NM_016023.5	ENSP00000384190.4

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

GnomAD2 exomes

AF:

0.000158

AC:

AN:

209016

AF XY:

0.000143

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 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

African (AFR)

AF:

0.00

AC:

AN:

32672

American (AMR)

AF:

0.000989

AC:

AN:

40440

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25448

East Asian (EAS)

AF:

0.00

AC:

AN:

38752

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000210

AC:

AN:

1096918

Other (OTH)

AF:

0.000118

AC:

AN:

59354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41406

American (AMR)

AF:

0.000459

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67966

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000976

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

May 03, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 24, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 05, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Apr 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs368313959, gnomAD 0.08%). 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. ClinVar contains an entry for this variant (Variation ID: 375701). For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Epilepsy;C0432072:Dysmorphic features;C3714756:Intellectual disability

Pathogenic:1

Jan 09, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 17, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.84

PhyloP100

0.90

Vest4

0.39

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over