NM_138348.6:c.22C>T

Variant names:

• chr5-14664847-C-T
• rs1735786455
• NM_138348.6:c.22C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138348.6(OTULIN):​c.22C>T​(p.Gln8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTULIN NM_138348.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.10
• Publications: 0 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-DT (HGNC:55368): (OTULIN divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-14664847-C-T is Pathogenic according to our data. Variant chr5-14664847-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1027708.Status of the report is criteria_provided_single_submitter, 1 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.22C>T	p.Gln8*	stop_gained	Exon 1 of 7	NP_612357.4
	OTULIN-DT	NR_168439.1		n.-243G>A		upstream_gene	N/A
	OTULIN-DT	NR_168440.1		n.-243G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.22C>T	p.Gln8*	stop_gained	Exon 1 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.22C>T	p.Gln8*	stop_gained	Exon 1 of 8	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000881544.1		c.22C>T	p.Gln8*	stop_gained	Exon 1 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1062644 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 504128

African (AFR) AF: 0.00 AC: 0 AN: 22338

American (AMR) AF: 0.00 AC: 0 AN: 9978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12624

East Asian (EAS) AF: 0.00 AC: 0 AN: 24302

South Asian (SAS) AF: 0.00 AC: 0 AN: 20792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2796

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 907984

Other (OTH) AF: 0.00 AC: 0 AN: 41486

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.53	D
PhyloP100		3.1
Vest4		0.092
GERP RS		3.8
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=19/181	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: rs1735786455; hg19: chr5-14664956;