NM_138348.6:c.815T>C

Variant names:

• chr5-14690259-T-C
• rs886037885
• NM_138348.6:c.815T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_138348.6(OTULIN):​c.815T>C​(p.Leu272Pro) variant causes a missense change involving the alteration of a 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTULIN NM_138348.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• Publications: 15 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• PP5: Variant 5-14690259-T-C is Pathogenic according to our data. Variant chr5-14690259-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 254124.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.815T>C	p.Leu272Pro	missense	Exon 6 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.815T>C	p.Leu272Pro	missense	Exon 6 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.815T>C	p.Leu272Pro	missense	Exon 6 of 8	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000881544.1		c.689T>C	p.Leu230Pro	missense	Exon 5 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.073	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.61		Gain of disorder (P = 0.0092)
MVP		0.64
MPC		2.5
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.91
Mutation Taster		=11/89	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: rs886037885; hg19: chr5-14690368;