rs139848059

Variant names:

• chr5-14664879-C-A
• rs139848059
• NM_138348.6:c.54C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-14664879-C-A
• chr5-14664879-C-G
• chr5-14664879-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_138348.6(OTULIN):​c.54C>A​(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000959 in 1,042,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: OTULIN NM_138348.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.82
• 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 Gene-Disease associations (from GenCC):

• autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• hereditary periodic fever syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-2.82 with no splicing effect.

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.54C>A	p.Ala18Ala	synonymous	Exon 1 of 7	NP_612357.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTULIN	ENST00000284274.5	TSL:1 MANE Select	c.54C>A	p.Ala18Ala	synonymous	Exon 1 of 7	ENSP00000284274.4	Q96BN8
	OTULIN	ENST00000850613.1		c.54C>A	p.Ala18Ala	synonymous	Exon 1 of 8	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000881544.1		c.54C>A	p.Ala18Ala	synonymous	Exon 1 of 6	ENSP00000551603.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 9.59e-7 AC: 1 AN: 1042860 Hom.: 0 Cov.: 30 AF XY: 0.00000203 AC XY: 1 AN XY: 492668

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21608

American (AMR) AF: 0.00 AC: 0 AN: 7494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12314

East Asian (EAS) AF: 0.00 AC: 0 AN: 22824

South Asian (SAS) AF: 0.00 AC: 0 AN: 19526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2694

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 896334

Other (OTH) AF: 0.00 AC: 0 AN: 40558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.1
DANN	Benign	0.91
PhyloP100		-2.8
PromoterAI		0.0076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139848059; hg19: chr5-14664988;