5-14664712-G-A

Variant summary

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

The ENST00000503023.2(OTULIN):c.-114G>A variant causes a 5 prime UTR, NMD transcript 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 5_prime_UTR, NMD_transcript
• 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]

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/exons	MANE	UniProt
OTULIN	NM_138348.6			upstream_gene_variant		ENST00000284274.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTULIN	ENST00000503023.2	c.-114G>A		5_prime_UTR_variant, NMD_transcript_variant	1/6	5
OTULIN	ENST00000284274.5			upstream_gene_variant		1	NM_138348.6	P1
OTULIN	ENST00000507335.1			upstream_gene_variant		2

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

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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;