rs886037886

Variant names:

• chr5-14687568-AC-A
• rs886037886
• NM_138348.6:c.517delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_138348.6(OTULIN):​c.517delC​(p.Gly174AspfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic,risk factor (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTULIN NM_138348.6 frameshift
• Clinical Significance: Pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.03
• Publications: 9 publications found

Genes affected

OTULIN (HGNC:25118): (OTU deubiquitinase with linear linkage specificity) This gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked, or linear, ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa B signaling pathway in the context of immunity and inflammation. Mutations in this gene cause a potentially fatal autoinflammatory syndrome in human patients. [provided by RefSeq, Sep 2016]

OTULIN Gene-Disease associations (from GenCC):

• autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary periodic fever syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-14687568-AC-A is Pathogenic according to our data. Variant chr5-14687568-AC-A is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 254125.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138348.6. 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
	OTULIN	NM_138348.6	MANE Select	c.517delC	p.Gly174AspfsTer2	frameshift	Exon 5 of 7	NP_612357.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.517delC	p.Gly174AspfsTer2	frameshift	Exon 5 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.517delC	p.Gly174AspfsTer2	frameshift	Exon 5 of 8	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000955678.1		c.517delC	p.Gly174AspfsTer2	frameshift	Exon 5 of 6	ENSP00000625737.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (1)
-	-	-	Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=1/199	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: rs886037886; hg19: chr5-14687677;