chr8-91070346-A-G

Position:

chr8-91070346-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000285420.8(OTUD6B):c.52A>G(p.Arg18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,613,194 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

OTUD6B
ENST00000285420.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.513

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:

OTUD6B-AS1 (HGNC:):

OTUD6B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003791839).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00108 (164/152298) while in subpopulation AFR AF= 0.00344 (143/41572). AF 95% confidence interval is 0.00298. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
OTUD6B	NM_016023.5 linkuse as main transcript	c.-39A>G	5_prime_UTR_variant	1/7	ENST00000404789.8	NP_057107.4	Q8N6M0-1A0A087X0W9
OTUD6B	NM_001416022.1 linkuse as main transcript	c.-39A>G	5_prime_UTR_variant	1/6		NP_001402951.1
OTUD6B	NM_001286745.3 linkuse as main transcript	c.-482A>G	5_prime_UTR_variant	1/8		NP_001273674.1	Q8N6M0-2
OTUD6B	XM_047421864.1 linkuse as main transcript	c.-39A>G	5_prime_UTR_variant	1/4		XP_047277820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789 linkuse as main transcript	c.-39A>G		5_prime_UTR_variant	1/7	1	NM_016023.5	ENSP00000384190.4		Q8N6M0-1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00350

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000366

AC:

AN:

248344

Hom.:

AF XY:

0.000268

AC XY:

AN XY:

134368

show subpopulations

Gnomad AFR exome

AF:

0.00458

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1460896

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.00275

Gnomad4 AMR exome

AF:

0.000314

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:

0.0000369

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.00108

AC:

164

AN:

152298

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000503

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 12, 2019

Variant summary: OTUD6B c.52A>G (p.Arg18Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 248344 control chromosomes, predominantly at a frequency of 0.0046 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in OTUD6B causing Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.52A>G in individuals affected with Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 11, 2018

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

OTUD6B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.2

DANN

Benign

0.61

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.26

T;.

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.19

.;N

REVEL

Benign

0.025

Sift

Benign

0.50

.;T

Sift4G

Benign

0.56

T;T

Vest4

0.090

MVP

0.36

MPC

0.019

ClinPred

0.019

GERP RS

-9.6

gMVP

0.084

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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