5-14664862-C-T

Variant names:

• chr5-14664862-C-T
• rs2126808718
• NM_138348.6:c.37C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138348.6(OTULIN):​c.37C>T​(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 1,055,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: OTULIN NM_138348.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077005655).

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.37C>T	p.Pro13Ser	missense	Exon 1 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.37C>T	p.Pro13Ser	missense	Exon 1 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.37C>T	p.Pro13Ser	missense	Exon 1 of 8	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000881544.1		c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000663 AC: 7 AN: 1055902 Hom.: 0 Cov.: 30 AF XY: 0.00000400 AC XY: 2 AN XY: 500092

African (AFR) AF: 0.00 AC: 0 AN: 22112

American (AMR) AF: 0.00 AC: 0 AN: 8906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12554

East Asian (EAS) AF: 0.00 AC: 0 AN: 23842

South Asian (SAS) AF: 0.00 AC: 0 AN: 20286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2752

European-Non Finnish (NFE) AF: 0.00000774 AC: 7 AN: 904174

Other (OTH) AF: 0.00 AC: 0 AN: 41222

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.77	N
REVEL	Benign	0.032
Sift	Benign	0.090	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.10		Gain of glycosylation at P13 (P = 0.0217)
MVP		0.082
MPC		0.89
ClinPred		0.24	T
GERP RS		2.1
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.28
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2126808718; hg19: chr5-14664971;