X-48923659-A-AT

Position:

• chrX-48923659-A-AT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001136157.2(OTUD5):​c.1552_1553insA​(p.Ile518AsnfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTUD5 NM_001136157.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0876 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD5	NM_001136157.2	c.1552_1553insA	p.Ile518AsnfsTer13	frameshift_variant	8/9	ENST00000376488.8	NP_001129629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD5	ENST00000376488.8	c.1552_1553insA	p.Ile518AsnfsTer13	frameshift_variant	8/9	1	NM_001136157.2	ENSP00000365671	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2024

The c.1567dupA (p.I523Nfs*13) alteration, located in coding exon 8 of the OTUD5 gene, consists of a duplication of A at position 1567, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the OTUD5 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 8.5% of the protein. The exact functional effect of this alteration is unknown. Based on data from the Genome Aggregation Database (gnomAD), the OTUD5 c.1567dupA alteration was not observed, with coverage at this position. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48780936;