5-14664886-CCGGCGCGGGAGGCGGCGGCCA-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BA1

The NM_138348.6(OTULIN):c.72_92del(p.Glu24_Arg30del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,190,212 control chromosomes in the GnomAD database, including 330 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P21P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (170 hom., cov: 34)
  • Exomes 𝑓: 0.0044 (160 hom.)
• Consequence: OTULIN NM_138348.6 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.13

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 Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_138348.6.
• BP6: Variant 5-14664886-CCGGCGCGGGAGGCGGCGGCCA-C is Benign according to our data. Variant chr5-14664886-CCGGCGCGGGAGGCGGCGGCCA-C is described in ClinVar as [Benign]. Clinvar id is 1165553.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTULIN	NM_138348.6	c.72_92del	p.Glu24_Arg30del	inframe_deletion	1/7	ENST00000284274.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTULIN	ENST00000284274.5	c.72_92del	p.Glu24_Arg30del	inframe_deletion	1/7	1	NM_138348.6	P1
OTULIN	ENST00000507335.1	n.166_186del		non_coding_transcript_exon_variant	1/2	2
OTULIN	ENST00000503023.2	c.72_92del	p.Glu24_Arg30del	inframe_deletion, NMD_transcript_variant	1/6	5
OTULIN	ENST00000697367.1	c.72_92del	p.Glu24_Arg30del	inframe_deletion, NMD_transcript_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4314 AN: 151006 Hom.: 169 Cov.: 34

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0169

Gnomad FIN AF: 0.0000991

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.0227

GnomAD3 exomes AF: 0.00285 AC: 6 AN: 2102 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1230

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00443 AC: 4601 AN: 1039098 Hom.: 160 AF XY: 0.00425 AC XY: 2084 AN XY: 490630

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.00771

Gnomad4 ASJ exome AF: 0.00261

Gnomad4 EAS exome AF: 0.00124

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00976

GnomAD4 genome AF: 0.0286 AC: 4325 AN: 151114 Hom.: 170 Cov.: 34 AF XY: 0.0272 AC XY: 2011 AN XY: 73850

Gnomad4 AFR AF: 0.0934

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0000991

Gnomad4 NFE AF: 0.00214

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0168 Hom.: 10

Asia WGS AF: 0.0130 AC: 44 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199656228; hg19: chr5-14664995;