chrX-48923964-C-T

Variant names:

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

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>A​(p.Arg451Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts 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. R451P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OTUD5 NM_001136157.2 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.26724347).

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>A	p.Arg451Gln	missense	Exon 7 of 9	NP_001129629.1	Q96G74-5
	OTUD5	NM_017602.4		c.1367G>A	p.Arg456Gln	missense	Exon 7 of 9	NP_060072.1	Q96G74-1
	OTUD5	NM_001136158.2		c.1352G>A	p.Arg451Gln	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>A	p.Arg451Gln	missense	Exon 7 of 9	ENSP00000365671.3	Q96G74-5
	OTUD5	ENST00000156084.8	TSL:1	c.1367G>A	p.Arg456Gln	missense	Exon 7 of 9	ENSP00000156084.4	Q96G74-1
	OTUD5	ENST00000396743.7	TSL:1	c.1352G>A	p.Arg451Gln	missense	Exon 7 of 10	ENSP00000379969.3	Q96G74-5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096169 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361647

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 35041

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30118

South Asian (SAS) AF: 0.00 AC: 0 AN: 53766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841047

Other (OTH) AF: 0.0000217 AC: 1 AN: 46017

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.060
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.33	B
Vest4		0.17
MutPred		0.24		Loss of MoRF binding (P = 0.0444)
MVP		0.76
MPC		1.7
ClinPred		0.87	D
GERP RS		4.4
Varity_R		0.25
gMVP		0.74
Mutation Taster		=77/23	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;