NM_138348.6:c.45G>A

Variant names:

• chr5-14664870-G-A
• NM_138348.6:c.45G>A
• OTULIN p.Ala15Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP7

The NM_138348.6(OTULIN):c.45G>A (p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTULIN NM_138348.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.776
• 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: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_138348.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTULIN NM_138348.6	MANE Select	c.45G>A p.Ala15Ala	synonymous	Exon 1 of 7	Prot: NP_612357.4

OTULIN NM_138348.6

MANE Select

HGVSc / HGVSpc.45G>Ap.Ala15Ala

Exon rankExon 1 of 7

synonymous

Prot: NP_612357.4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTULIN ENST00000284274.5	TSL:1MANE Select	c.45G>A p.Ala15Ala	synonymous	Exon 1 of 7	Prot: ENSP00000284274.4 UniProt:
	OTULIN ENST00000850613.1		c.45G>A p.Ala15Ala	synonymous	Exon 1 of 8	Prot: ENSP00000520900.1 UniProt:
	OTULIN ENST00000881544.1		c.45G>A p.Ala15Ala	synonymous	Exon 1 of 6	Prot: ENSP00000551603.1 UniProt:

OTULIN ENST00000284274.5

TSL:1MANE Select

HGVSc / HGVSpc.45G>Ap.Ala15Ala

Exon rankExon 1 of 7

synonymous

Prot: ENSP00000284274.4UniProt: Q96BN8

OTULIN ENST00000850613.1

HGVSc / HGVSpc.45G>Ap.Ala15Ala

Exon rankExon 1 of 8

synonymous

Prot: ENSP00000520900.1UniProt: Q96BN8

OTULIN ENST00000881544.1

HGVSc / HGVSpc.45G>Ap.Ala15Ala

Exon rankExon 1 of 6

synonymous

Prot: ENSP00000551603.1UniProt: A0ACI8T2H6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1048270	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:35

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.27
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.96
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
PhyloP100	Benign	-0.78
PromoterAI	N/A	0.0042	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr5-14664979;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar