SETMAR

protein-coding

SET domain and mariner transposase fusion gene, the group of DNA transposon derived genes|SET domain containing

Gene summary

This gene encodes a fusion protein that contains an N-terminal histone-lysine N-methyltransferase domain and a C-terminal mariner transposase domain. The encoded protein binds DNA and functions in DNA repair activities including non-homologous end joining and double strand break repair. The SET domain portion of this protein specifically methylates histone H3 lysines 4 and 36. This gene exists as a fusion gene only in anthropoid primates, other organisms lack mariner transposase domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

MANE transcript

NM_006515.4

Inheritance

—

ClinVar variants

U:67B:6

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr3:4,303,332-4,317,265

External References & Databases

Ensembl (ENSG00000170364)

Transcript & Mutation Effects

hg38 • Region Span ~13.9 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 SETMAR variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 66

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006515.4. 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			1 clinvar	3 clinvar		4
missense			64 clinvar	3 clinvar		67
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	67	6	0	73

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006515.4	RefSeq	NP_006506.3	3	MANE Select
ENST00000358065.5	Ensembl	ENSP00000373354.3	3	MANE Select
NM_001243723.2	RefSeq	NP_001230652.1	4	Standard
NM_001276325.2	RefSeq	NP_001263254.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications

Biological Process

DNA double-strand break processing
DNA catabolic process, endonucleolytic
double-strand break repair via nonhomologous end joining
cell population proliferation
histone H3-K36 methylation

Molecular Function

single-stranded DNA endodeoxyribonuclease activity
DNA binding
double-stranded DNA binding
single-stranded DNA binding
endonuclease activity

Cellular Component

condensed chromosome
nucleus
nucleolus
site of double-strand break

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358065
Coding exons: 3
Length: 14264
Individuals with no LoFs: 125629
Homozygous LoFs: 2
Heterozygous LoFs: 95
Defined: 125726
p: 0.000386

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.263	362	376	0.962	0.0000208	4463
Missense (PolyPhen)		71	65.409	1.0855		831
Synonymous	0.206	137	140	0.978	0.00000813	1296
Loss of Function	1.24	8	12.8	0.626	7.61e-7	175

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00027	rare
South Asian	0.0013	0.0012	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein derived from the fusion of a methylase with the transposase of an Hsmar1 transposon that plays a role in DNA double-strand break repair, stalled replication fork restart and DNA integration. DNA-binding protein, it is indirectly recruited to sites of DNA damage through protein-protein interactions. Has also kept a sequence-specific DNA-binding activity recognizing the 19-mer core of the 5'-terminal inverted repeats (TIRs) of the Hsmar1 element and displays a DNA nicking and end joining activity (PubMed:16332963, PubMed:16672366, PubMed:17877369, PubMed:17403897, PubMed:18263876, PubMed:22231448, PubMed:24573677, PubMed:20521842). In parallel, has a histone methyltransferase activity and methylates 'Lys-4' and 'Lys-36' of histone H3. Specifically mediates dimethylation of H3 'Lys-36' at sites of DNA double-strand break and may recruit proteins required for efficient DSB repair through non-homologous end-joining (PubMed:16332963, PubMed:21187428, PubMed:22231448). Also regulates replication fork processing, promoting replication fork restart and regulating DNA decatenation through stimulation of the topoisomerase activity of TOP2A (PubMed:18790802, PubMed:20457750). {ECO:0000269|PubMed:16332963, ECO:0000269|PubMed:16672366, ECO:0000269|PubMed:17403897, ECO:0000269|PubMed:17877369, ECO:0000269|PubMed:18790802, ECO:0000269|PubMed:20457750, ECO:0000269|PubMed:20521842, ECO:0000269|PubMed:21187428, ECO:0000269|PubMed:22231448, ECO:0000269|PubMed:24573677, ECO:0000303|PubMed:18263876}.;

Recessive Scores

pRec: 0.0930

Intolerance Scores

LoFtool: 0.318
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.974

Gene Damage Prediction

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