chr5-14664712-G-A

Variant names:

• chr5-14664712-G-A
• rs250435
• ENST00000503023.2:n.-114G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000503023.2(OTULIN):​n.-114G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 1,036,328 control chromosomes in the GnomAD database, including 446,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.93 (65348 hom., cov: 35)
  • Exomes 𝑓: 0.93 (381079 hom.)
• Consequence: OTULIN ENST00000503023.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.244

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-14664712-G-A is Benign according to our data. Variant chr5-14664712-G-A is described in ClinVar as [Benign]. Clinvar id is 2688224.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTULIN	NM_138348.6	c.-114G>A		upstream_gene_variant		ENST00000284274.5	NP_612357.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTULIN	ENST00000284274.5	c.-114G>A		upstream_gene_variant		1	NM_138348.6	ENSP00000284274.4

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140906 AN: 152094 Hom.: 65321 Cov.: 35

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.912

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.930

GnomAD4 exome AF: 0.928 AC: 820685 AN: 884126 Hom.: 381079 Cov.: 13 AF XY: 0.928 AC XY: 386481 AN XY: 416326

Gnomad4 AFR exome AF: 0.919

Gnomad4 AMR exome AF: 0.966

Gnomad4 ASJ exome AF: 0.937

Gnomad4 EAS exome AF: 0.800

Gnomad4 SAS exome AF: 0.918

Gnomad4 FIN exome AF: 0.941

Gnomad4 NFE exome AF: 0.930

Gnomad4 OTH exome AF: 0.926

GnomAD4 genome AF: 0.926 AC: 140978 AN: 152202 Hom.: 65348 Cov.: 35 AF XY: 0.926 AC XY: 68867 AN XY: 74406

Gnomad4 AFR AF: 0.918

Gnomad4 AMR AF: 0.957

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.912

Gnomad4 FIN AF: 0.944

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.921

Alfa AF: 0.920 Hom.: 3032

Bravo AF: 0.929

Asia WGS AF: 0.846 AC: 2931 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs250435; hg19: chr5-14664821;