SENP6

protein-coding

SUMO specific peptidase 6, the group of SUMO specific peptidases

Gene summary

Ubiquitin-like molecules (UBLs), such as SUMO1 (UBL1; MIM 601912), are structurally related to ubiquitin (MIM 191339) and can be ligated to target proteins in a similar manner as ubiquitin. However, covalent attachment of UBLs does not result in degradation of the modified proteins. SUMO1 modification is implicated in the targeting of RANGAP1 (MIM 602362) to the nuclear pore complex, as well as in stabilization of I-kappa-B-alpha (NFKBIA; MIM 164008) from degradation by the 26S proteasome. Like ubiquitin, UBLs are synthesized as precursor proteins, with 1 or more amino acids following the C-terminal glycine-glycine residues of the mature UBL protein. Thus, the tail sequences of the UBL precursors need to be removed by UBL-specific proteases, such as SENP6, prior to their conjugation to target proteins (Kim et al., 2000 [PubMed 10799485]). SENPs also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008 [PubMed 18799455]).[supplied by OMIM, Jun 2009]

MANE transcript

NM_015571.4

Inheritance

—

ClinVar variants

U:153B:11

Top phenotype

Synophrys

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr6:75,601,509-75,718,281

External References & Databases

Ensembl (ENSG00000112701)

Transcript & Mutation Effects

hg38 • Region Span ~116.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SENP6 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 134

not providedTotal: 9

SynophrysTotal: 1

Delayed speech and language developmentTotal: 1

High, narrow palateTotal: 1

EpicanthusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015571.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	2 clinvar	2 clinvar	7
missense			138 clinvar	6 clinvar		144
nonsense			3 clinvar	1 clinvar		4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	153	9	2	164

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 85 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015571.4	RefSeq	NP_056386.2	24	MANE Select
ENST00000447266.7	Ensembl	ENSP00000402527.2	24	MANE Select
NM_001100409.3	RefSeq	NP_001093879.1	23	Standard
NM_001304792.2	RefSeq	NP_001291721.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein sumoylation
protein desumoylation
protein modification by small protein removal
regulation of spindle assembly
regulation of kinetochore assembly

Molecular Function

protein binding
SUMO-specific endopeptidase activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447266
Coding exons: 24
Length: 116773
Individuals with no LoFs: 124762
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 124780
p: 0.0000721

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.999	500	567	0.882	0.0000288	7386
Missense (PolyPhen)		154	221.48	0.69531		2935
Synonymous	0.0423	190	191	0.996	0.00000962	1966
Loss of Function	6.42	7	61.3	0.114	0.00000370	749

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00023	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000099	0.000097	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly- SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Desumoylates also RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. {ECO:0000269|PubMed:16912044, ECO:0000269|PubMed:17000875, ECO:0000269|PubMed:18799455, ECO:0000269|PubMed:20212317, ECO:0000269|PubMed:20705237, ECO:0000269|PubMed:21148299}.;

Recessive Scores

pRec: 0.0827

Intolerance Scores

LoFtool: 0.558
RVIS EVS: 0.36
RVIS percentile EVS: 74.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.902

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium