NM_138348.6:c.-3C>T

Variant names:

• chr5-14664823-C-T
• rs1404573525
• NM_138348.6:c.-3C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_138348.6(OTULIN):​c.-3C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,217,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: OTULIN NM_138348.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.928
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-14664823-C-T is Benign according to our data. Variant chr5-14664823-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3040592.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138348.6. 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.-3C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_612357.4
	OTULIN	NM_138348.6	MANE Select	c.-3C>T		5_prime_UTR	Exon 1 of 7	NP_612357.4
	OTULIN-DT	NR_168439.1		n.-219G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.-3C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.-3C>T		5_prime_UTR	Exon 1 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.-3C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000520900.1	Q96BN8

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000375 AC: 4 AN: 1065668 Hom.: 0 Cov.: 30 AF XY: 0.00000395 AC XY: 2 AN XY: 506102

African (AFR) AF: 0.00 AC: 0 AN: 22448

American (AMR) AF: 0.00 AC: 0 AN: 11018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12562

East Asian (EAS) AF: 0.00 AC: 0 AN: 24576

South Asian (SAS) AF: 0.00 AC: 0 AN: 21236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.00000440 AC: 4 AN: 909188

Other (OTH) AF: 0.00 AC: 0 AN: 41456

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	OTULIN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		0.93
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1404573525; hg19: chr5-14664932;