Genetic Variant NM_138348.6:c.44C>A (chr5-14664869-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138348.6(OTULIN):c.44C>A(p.Ala15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTULIN
NM_138348.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.353

Publications

0 publications found

Variant links:

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

OTULIN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046270043).

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.44C>A	p.Ala15Glu	missense	Exon 1 of 7	NP_612357.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.44C>A	p.Ala15Glu	missense	Exon 1 of 7	ENSP00000284274.4	Q96BN8
OTULIN	ENST00000850613.1		c.44C>A	p.Ala15Glu	missense	Exon 1 of 8	ENSP00000520900.1	Q96BN8
OTULIN	ENST00000881544.1		c.44C>A	p.Ala15Glu	missense	Exon 1 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1047690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

495388

African (AFR)

AF:

0.00

AC:

AN:

21826

American (AMR)

AF:

0.00

AC:

AN:

7946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12396

East Asian (EAS)

AF:

0.00

AC:

AN:

23202

South Asian (SAS)

AF:

0.00

AC:

AN:

19830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

899258

Other (OTH)

AF:

0.00

AC:

AN:

40802

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0084

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.39

M_CAP

Benign

0.068

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-0.35

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.27

REVEL

Benign

0.012

Sift

Benign

0.10

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.13

MutPred

0.21

Gain of solvent accessibility (P = 0.006)

MVP

0.043

MPC

0.99

ClinPred

0.13

GERP RS

1.1

PromoterAI

0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.40

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over