THAP11

protein-coding

THAP domain containing 11, the group of THAP domain containing

Gene summary

The protein encoded by this gene contains a THAP domain, which is a conserved DNA-binding domain that has striking similarity to the site-specific DNA-binding domain (DBD) of Drosophila P element transposases. [provided by RefSeq, Jul 2008]

MANE transcript

NM_020457.3

Inheritance

AR, AD

ClinVar variants

P:1U:54B:24

Top phenotype

Allelic with Methylmalonic aciduria, cblC type-like (AR)

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr16:67,842,320-67,844,195

External References & Databases

Ensembl (ENSG00000168286)

Transcript & Mutation Effects

hg38 • Region Span ~1.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inborn disorder of cobalamin metabolism and transportLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019220

Submitter: PanelApp Australia

methylmalonic aciduria and homocystinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016826

Submitter: ClinGen

*THAP11* was first reported in relation to autosomal recessive methylmalonic acidemia with homocystinuria in 2017 (Quintana AM, et al., 2017, PMID: 28449119). *THAP11* encodes a transcription factor that plays a central role for embryogenesis and the pluripotency of embryonic stem cells. It forms a complex with HCF-1, a transcriptional coregulator essential for cell-cycle progression and cell proliferation, and together they regulate the expression of *MMACHC* among other targets. Only one variant (Phe80Leu) has been reported in one proband (PMID: 28449119), resulting in loss of binding to the *MMACHC* promoter, and thus resulting in metabolic abnormalities similar to *MMACHC* deficiency, such as reduced adenosylcobalamin and methylcobalamin as well as decreased [14C]propionate and [14C]methyltetrahydrofolate incorporation. Experimentally, this gene-disease relationship is supported by its interaction with *HCFC1* and their function in transcriptional regulation (PMID: 31905202) which was altered in patient cells (PMID: 28449119) and HEK293 cells expressing the Phe80Leu variant (PMID: 31905202). Additionally, knockdown in zebrafish (PMID: 28449119) resulted in phenotypes similar to other cobalamin C deficiencies, and a Phe80Leu knockin mouse model recapitulated the metabolic abnormalities observed in the patient (PMID: 35013307). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Clinical Genomic Database (CGD)

Allelic with Methylmalonic aciduria, cblC type-like (AR)AD

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: A described individual was affected with severe neurologic sequelae and while treatment (eg, with protein restriction,betaine, folic acid, hydroxocobalamin injection, and pyridoxine) was not effective, it would be logical to implement such management for this type of biochemical condition

Refs: 28449119; 37148549; 38757579

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THAP11 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 133

not specifiedTotal: 31

THAP11-related disorderTotal: 20

Spinocerebellar ataxia 51Total: 1

Disorders of Intracellular Cobalamin MetabolismTotal: 1

Methylmalonic aciduria and homocystinuria, cb1L typeTotal: 1

Methylmalonic acidemia with homocystinuria, type cblXTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020457.3. 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			9 clinvar	19 clinvar	4 clinvar	32
missense		1 clinvar	45 clinvar	1 clinvar		47
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	1	54	20	4	79

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020457.3	RefSeq	NP_065190.2	1	MANE Select
ENST00000303596.3	Ensembl	ENSP00000304689.1	1	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
thap11	Danio rerio	Structure: ceratobranchial cartilage Quality: immature abnormal

Gene / Model

Organism

Observed Phenotype

thap11

Danio rerio

Structure: ceratobranchial cartilage

Quality: immature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA binding
protein binding

Cellular Component

nucleoplasm
cytoplasm
intercellular bridge

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303596
Coding exons: 1
Length: 1885
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.15	98	179	0.547	0.00000822	1998
Missense (PolyPhen)		3	25.158	0.11924		287
Synonymous	-3.08	110	75.9	1.45	0.00000371	656
Loss of Function	2.66	1	10.1	0.0986	4.46e-7	104

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional repressor that plays a central role for embryogenesis and the pluripotency of embryonic stem (ES) cells. Sequence-specific DNA-binding factor that represses gene expression in pluripotent ES cells by directly binding to key genetic loci and recruiting epigenetic modifiers (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.358
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.613

Gene Damage Prediction

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