8-91070370-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000285420.8(OTUD6B):​c.76G>T​(p.Gly26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G26R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OTUD6B ENST00000285420.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.29632 (below the threshold of 3.09). Trascript score misZ: -0.53276 (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37056234).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000285420.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD6B	NM_016023.5	MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 7	NP_057107.4
	OTUD6B	NM_001416022.1		c.-15G>T		5_prime_UTR	Exon 1 of 6	NP_001402951.1
	OTUD6B	NM_001286745.3		c.-458G>T		5_prime_UTR	Exon 1 of 8	NP_001273674.1	Q8N6M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD6B	ENST00000285420.8	TSL:1	c.76G>T	p.Gly26Trp	missense	Exon 1 of 7	ENSP00000285420.4	A0A087X0W9
	OTUD6B	ENST00000617869.4	TSL:1	c.76G>T	p.Gly26Trp	missense	Exon 1 of 7	ENSP00000483706.1	A0A087X0W9
	OTUD6B	ENST00000404789.8	TSL:1 MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 7	ENSP00000384190.4	Q8N6M0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459728 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725892

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111068

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.10
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.55
MutPred		0.52		Loss of sheet (P = 0.0025)
MVP		0.28
MPC		0.068
ClinPred		0.37	T
GERP RS		0.44
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.057
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs186307892; hg19: chr8-92082598;