chr5-14664712-G-A

Variant names:

• chr5-14664712-G-A
• rs250435
• ENST00000921417.1:c.-114G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000921417.1(OTULIN):​c.-114G>A variant causes a 5 prime UTR 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 ENST00000921417.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.244
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000921417.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	NM_138348.6	MANE Select	c.-114G>A		upstream_gene	N/A	NP_612357.4
	OTULIN-DT	NR_168439.1		n.-108C>T		upstream_gene	N/A
	OTULIN-DT	NR_168440.1		n.-108C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	ENST00000921417.1		c.-114G>A		5_prime_UTR	Exon 1 of 7	ENSP00000591476.1
	OTULIN	ENST00000955678.1		c.-114G>A		5_prime_UTR	Exon 1 of 6	ENSP00000625737.1
	OTULIN	ENST00000503023.2	TSL:5	n.-114G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000427016.1	D6RD57

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

African (AFR) AF: 0.919 AC: 15714 AN: 17100

American (AMR) AF: 0.966 AC: 3736 AN: 3866

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 7562 AN: 8068

East Asian (EAS) AF: 0.800 AC: 10444 AN: 13050

South Asian (SAS) AF: 0.918 AC: 15107 AN: 16452

European-Finnish (FIN) AF: 0.941 AC: 11007 AN: 11692

Middle Eastern (MID) AF: 0.951 AC: 1940 AN: 2040

European-Non Finnish (NFE) AF: 0.930 AC: 725843 AN: 780186

Other (OTH) AF: 0.926 AC: 29332 AN: 31672

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

African (AFR) AF: 0.918 AC: 38133 AN: 41552

American (AMR) AF: 0.957 AC: 14638 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3225 AN: 3470

East Asian (EAS) AF: 0.817 AC: 4208 AN: 5150

South Asian (SAS) AF: 0.912 AC: 4407 AN: 4830

European-Finnish (FIN) AF: 0.944 AC: 10015 AN: 10608

Middle Eastern (MID) AF: 0.976 AC: 285 AN: 292

European-Non Finnish (NFE) AF: 0.930 AC: 63232 AN: 67976

Other (OTH) AF: 0.921 AC: 1948 AN: 2114

Alfa AF: 0.920 Hom.: 3032

Bravo AF: 0.929

Asia WGS AF: 0.846 AC: 2931 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.73
PhyloP100		-0.24
PromoterAI		-0.38	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs250435; hg19: chr5-14664821;