Genetic Variant NM_138348.6:c.54C>T (chr5-14664879-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_138348.6(OTULIN):c.54C>T(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000636 in 1,194,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

OTULIN
NM_138348.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.82

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 5-14664879-C-T is Benign according to our data. Variant chr5-14664879-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1926741.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.82 with no splicing effect.

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.54C>T	p.Ala18Ala	synonymous	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.54C>T	p.Ala18Ala	synonymous	Exon 1 of 7	ENSP00000284274.4	Q96BN8
OTULIN	ENST00000850613.1		c.54C>T	p.Ala18Ala	synonymous	Exon 1 of 8	ENSP00000520900.1	Q96BN8
OTULIN	ENST00000881544.1		c.54C>T	p.Ala18Ala	synonymous	Exon 1 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000465

AC:

AN:

4302

AF XY:

0.000396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000346

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000662

AC:

AN:

1042860

Hom.:

Cov.:

AF XY:

0.0000710

AC XY:

AN XY:

492668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21608

American (AMR)

AF:

0.00

AC:

AN:

7494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12314

East Asian (EAS)

AF:

0.00298

AC:

AN:

22824

South Asian (SAS)

AF:

0.00

AC:

AN:

19526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

896334

Other (OTH)

AF:

0.0000247

AC:

AN:

40558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.572

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00135

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67746

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Likely benign

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.5

(source)

DANN

Benign

0.95

PhyloP100

-2.8

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over