NM_001136157.2:c.1531G>A

Variant names:

• chrX-48923681-C-T
• NM_001136157.2:c.1531G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001136157.2(OTUD5):​c.1531G>A​(p.Ala511Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTUD5 NM_001136157.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11
• Publications: 0 publications found

Genes affected

OTUD5 (HGNC:25402): (OTU deubiquitinase 5) This gene encodes a member of the OTU (ovarian tumor) domain-containing cysteine protease superfamily. The OTU domain confers deubiquitinase activity and the encoded protein has been shown to suppress the type I interferon-dependent innate immune response by cleaving the polyubiquitin chain from an essential type I interferon adaptor protein. Cleavage results in disassociation of the adaptor protein from a downstream signaling complex and disruption of the type I interferon signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Oct 2008]

OTUD5 Gene-Disease associations (from GenCC):

• multiple congenital anomalies-neurodevelopmental syndrome, X-linked

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.994 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to multiple congenital anomalies-neurodevelopmental syndrome, X-linked, multiple congenital anomalies/dysmorphic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17749557).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136157.2. 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
	OTUD5	NM_001136157.2	MANE Select	c.1531G>A	p.Ala511Thr	missense	Exon 8 of 9	NP_001129629.1	Q96G74-5
	OTUD5	NM_017602.4		c.1546G>A	p.Ala516Thr	missense	Exon 8 of 9	NP_060072.1	Q96G74-1
	OTUD5	NM_001136158.2		c.1531G>A	p.Ala511Thr	missense	Exon 8 of 10	NP_001129630.1	Q96G74-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD5	ENST00000376488.8	TSL:1 MANE Select	c.1531G>A	p.Ala511Thr	missense	Exon 8 of 9	ENSP00000365671.3	Q96G74-5
	OTUD5	ENST00000156084.8	TSL:1	c.1546G>A	p.Ala516Thr	missense	Exon 8 of 9	ENSP00000156084.4	Q96G74-1
	OTUD5	ENST00000396743.7	TSL:1	c.1531G>A	p.Ala511Thr	missense	Exon 8 of 10	ENSP00000379969.3	Q96G74-5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.023
Sift	Benign	0.045	D
Sift4G	Benign	0.53	T
Polyphen		0.023	B
Vest4		0.19
MutPred		0.19		Loss of helix (P = 0.0626)
MVP		0.30
MPC		1.5
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.58
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chrX-48780958;