8-91070370-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000285420.8(OTUD6B):c.76G>A(p.Gly26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,612,012 control chromosomes in the GnomAD database, including 11 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: OTUD6B ENST00000285420.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.105

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051209033).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (198/152286) while in subpopulation NFE AF= 0.00219 (149/68018). AF 95% confidence interval is 0.0019. There are 0 homozygotes in gnomad4. There are 90 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTUD6B	NM_016023.5	c.-15G>A		5_prime_UTR_variant	1/7	ENST00000404789.8
OTUD6B	NM_001286745.3	c.-458G>A		5_prime_UTR_variant	1/8
OTUD6B	NM_001416022.1	c.-15G>A		5_prime_UTR_variant	1/6
OTUD6B	XM_047421864.1	c.-15G>A		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTUD6B	ENST00000404789.8	c.-15G>A		5_prime_UTR_variant	1/7	1	NM_016023.5

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00133 AC: 328 AN: 245972 Hom.: 0 AF XY: 0.00150 AC XY: 199 AN XY: 132998

Gnomad AFR exome AF: 0.000509

Gnomad AMR exome AF: 0.000589

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000771

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00243 AC: 3550 AN: 1459726 Hom.: 11 Cov.: 31 AF XY: 0.00238 AC XY: 1731 AN XY: 725892

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000631

Gnomad4 ASJ exome AF: 0.000844

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000712

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74450

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00143

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00123 AC: 149

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 03, 2018

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.7
Dann	Uncertain	0.99
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.031	D;D
Vest4		0.21
MutPred		0.52		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.19
MPC		0.019
ClinPred		0.037	T
GERP RS		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.055

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: rs186307892; hg19: chr8-92082598;