chr5-14664830-G-A

Position:

• chr5-14664830-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138348.6(OTULIN):​c.5G>A​(p.Ser2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,067,560 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: OTULIN NM_138348.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062713146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTULIN	NM_138348.6	c.5G>A	p.Ser2Asn	missense_variant	1/7	ENST00000284274.5	NP_612357.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTULIN	ENST00000284274.5	c.5G>A	p.Ser2Asn	missense_variant	1/7	1	NM_138348.6	ENSP00000284274	P1
OTULIN	ENST00000507335.1	n.99G>A		non_coding_transcript_exon_variant	1/2	2
OTULIN	ENST00000697367.1	c.5G>A	p.Ser2Asn	missense_variant, NMD_transcript_variant	1/5			ENSP00000513279
OTULIN	ENST00000503023.2	c.5G>A	p.Ser2Asn	missense_variant, NMD_transcript_variant	1/6	5		ENSP00000427016

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000562 AC: 6 AN: 1067560 Hom.: 0 Cov.: 30 AF XY: 0.00000986 AC XY: 5 AN XY: 507128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000329

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.0000198 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2 of the OTULIN protein (p.Ser2Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OTULIN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.029
Sift	Benign	0.25	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.15
MutPred		0.15		Loss of phosphorylation at S2 (P = 0.0157);
MVP		0.13
MPC		0.79
ClinPred		0.020	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.20

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: rs749422586; hg19: chr5-14664939;