8-91070346-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.513

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-AS1 (HGNC:50466): (OTUD6B antisense RNA 1 (head to head))

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003791839).
• BP6: Variant 8-91070346-A-G is Benign according to our data. Variant chr8-91070346-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 711501.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTUD6B	NM_016023.5	c.-39A>G		5_prime_UTR_variant	1/7	ENST00000404789.8
OTUD6B	NM_001286745.3	c.-482A>G		5_prime_UTR_variant	1/8
OTUD6B	NM_001416022.1	c.-39A>G		5_prime_UTR_variant	1/6
OTUD6B	XM_047421864.1	c.-39A>G		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTUD6B	ENST00000404789.8	c.-39A>G		5_prime_UTR_variant	1/7	1	NM_016023.5

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152180 Hom.: 0 Cov.: 32

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: 91 AN: 248344 Hom.: 0 AF XY: 0.000268 AC XY: 36 AN XY: 134368

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.: 2 Cov.: 31 AF XY: 0.0000991 AC XY: 72 AN XY: 726624

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.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74476

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.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000503 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	In silico analysis supports 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, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.26	T;.
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.56	T;T
Vest4		0.090
MVP		0.36
MPC		0.019
ClinPred		0.019	T
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

Other links and lift over

dbSNP: rs199542428; hg19: chr8-92082574;