chr5-14664842-T-C

Variant names:

• chr5-14664842-T-C
• rs745608502
• NM_138348.6:c.17T>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_138348.6(OTULIN):​c.17T>C​(p.Met6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,214,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: OTULIN NM_138348.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.14

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28345567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTULIN	NM_138348.6	c.17T>C	p.Met6Thr	missense_variant	Exon 1 of 7	ENST00000284274.5	NP_612357.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTULIN	ENST00000284274.5	c.17T>C	p.Met6Thr	missense_variant	Exon 1 of 7	1	NM_138348.6	ENSP00000284274.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151820 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000245 AC: 26 AN: 1062928 Hom.: 0 Cov.: 30 AF XY: 0.0000277 AC XY: 14 AN XY: 504564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000483

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151820 Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 2 AN XY: 74152

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000413

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000101 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17T>C (p.M6T) alteration is located in exon 1 (coding exon 1) of the OTULIN gene. This alteration results from a T to C substitution at nucleotide position 17, causing the methionine (M) at amino acid position 6 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 6 of the OTULIN protein (p.Met6Thr). This variant has not been reported in the literature in individuals affected with OTULIN-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1378534). -

Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive Uncertain:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.17T>C(p.Met6Thr) variant in OTULIN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain significance. Computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster -Polymorphism) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position in OTULIN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 6 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). In absence of another reportable variant in OTULIN gene, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.0099	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.56
MutPred		0.35		Gain of phosphorylation at M6 (P = 0.0047);
MVP		0.21
MPC		2.1
ClinPred		0.68	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs745608502; hg19: chr5-14664951;