NM_001136157.2:c.1352G>C

Variant names:

• chrX-48923964-C-G
• rs1252713651
• NM_001136157.2:c.1352G>C

Variant summary

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

The NM_001136157.2(OTUD5):​c.1352G>C​(p.Arg451Pro) 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. 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: 3.57
• 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 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 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=0.34190696).

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.1352G>C	p.Arg451Pro	missense	Exon 7 of 9	NP_001129629.1	Q96G74-5
	OTUD5	NM_017602.4		c.1367G>C	p.Arg456Pro	missense	Exon 7 of 9	NP_060072.1	Q96G74-1
	OTUD5	NM_001136158.2		c.1352G>C	p.Arg451Pro	missense	Exon 7 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.1352G>C	p.Arg451Pro	missense	Exon 7 of 9	ENSP00000365671.3	Q96G74-5
	OTUD5	ENST00000156084.8	TSL:1	c.1367G>C	p.Arg456Pro	missense	Exon 7 of 9	ENSP00000156084.4	Q96G74-1
	OTUD5	ENST00000396743.7	TSL:1	c.1352G>C	p.Arg451Pro	missense	Exon 7 of 10	ENSP00000379969.3	Q96G74-5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Benign	0.069	T
Sift4G	Benign	0.10	T
Polyphen		0.83	P
Vest4		0.32
MutPred		0.26		Loss of MoRF binding (P = 0.0116)
MVP		0.73
MPC		2.0
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.67
gMVP		0.83
Mutation Taster		=64/36	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: rs1252713651; hg19: chrX-48781241;