8-91070370-G-A

Variant names:

• chr8-91070370-G-A
• rs186307892
• ENST00000285420.8:c.76G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: OTUD6B ENST00000285420.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051209033).
• BP6: Variant 8-91070370-G-A is Benign according to our data. Variant chr8-91070370-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1033385.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTUD6B	NM_016023.5	c.-15G>A		5_prime_UTR_variant	Exon 1 of 7	ENST00000404789.8	NP_057107.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789	c.-15G>A		5_prime_UTR_variant	Exon 1 of 7	1	NM_016023.5	ENSP00000384190.4

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 03, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Inborn genetic diseases Benign:1

Nov 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	.;N
REVEL	Benign	0.021
Sift	Pathogenic	0.0	.;D
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;