chr8-91078597-A-G

Variant names:

• chr8-91078597-A-G
• rs1064797103
• NM_016023.5:c.557A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_016023.5(OTUD6B):​c.557A>G​(p.Tyr186Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTUD6B NM_016023.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.50
• Publications: 4 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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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: -0.268 (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 8-91078597-A-G is Pathogenic according to our data. Variant chr8-91078597-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375704.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTUD6B	NM_016023.5	c.557A>G	p.Tyr186Cys	missense_variant	Exon 4 of 7	ENST00000404789.8	NP_057107.4
OTUD6B	NM_001416022.1	c.476A>G	p.Tyr159Cys	missense_variant	Exon 3 of 6		NP_001402951.1
OTUD6B	NM_001286745.3	c.254A>G	p.Tyr85Cys	missense_variant	Exon 5 of 8		NP_001273674.1
OTUD6B	XM_011517129.3	c.254A>G	p.Tyr85Cys	missense_variant	Exon 4 of 7		XP_011515431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTUD6B	ENST00000404789.8	c.557A>G	p.Tyr186Cys	missense_variant	Exon 4 of 7	1	NM_016023.5	ENSP00000384190.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451390 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 720922

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 43230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106446

Other (OTH) AF: 0.00 AC: 0 AN: 60050

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy;C0432072:Dysmorphic features;C3714756:Intellectual disability Pathogenic:1

Jan 09, 2017

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This missense variant was found in one family, homozygous in 3 affected siblings: 20yo male with moderate intellectual disability, epilepsy, dysmorphic features, arachnodactyly; 16yo male with mild intellectual disability, epilepsy, dysmorphic features, hyperextensibility; 14yo female with moderate intellectual disability, epilepsy, dysmorphic features, arachnodactyly, hyperexensibility. -

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

May 03, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.5	.;.;.;H
PhyloP100		8.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.3	.;.;D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	.;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.82
MutPred		0.73		.;.;.;Loss of phosphorylation at Y186 (P = 0.0176);
MVP		0.82
MPC		0.15
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.73
Mutation Taster		=17/83	disease causing (ClinVar)

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: rs1064797103; hg19: chr8-92090825; COSMIC: COSV53444006;