ZMYND11

protein-coding

zinc finger MYND-type containing 11, the group of Zinc fingers MYND-type|PHD finger proteins|Bromodomain containing|PWWP domain containing

Gene summary

The protein encoded by this gene was first identified by its ability to bind the adenovirus E1A protein. The protein localizes to the nucleus. It functions as a transcriptional repressor, and expression of E1A inhibits this repression. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001370100.5

Inheritance

ClinVar variants

P:89U:176B:79

Top phenotype

Intellectual developmental disorder, autosomal dominant 30

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr10:130,088-254,637

External References & Databases

Ensembl (ENSG00000015171)

Transcript & Mutation Effects

hg38 • Region Span ~124.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014486

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014486

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014486

Submitter: G2P

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*ZMYND11* was first reported in relation to autism in 2012 (Iossifov et al PMID:22542183), and in relation to an autosomal dominant syndromic complex disorder in 2014 (Coe et al PMID:25217958, Cobben et al PMID:25281490). Commonly reported features include developmental delay/intellectual disability, seizures, autistic behaviors, delayed speech and language development, behavioral issues (ADHD and aggressive behavior), dysmorphic facies (broad nose, thin lips, low set or posteriorly rotated ears, hypertelorism or deeply set eyes), and hand, foot, and digital abnormalities. Phenotypic features and severity are variable between probands. Twenty-five heterozygous predicted null, loss of function variants and 11 missense variants have been reported in 11 publications and are included in this curation (PMIDs: 34216016, 27626064, 22542183, 25217958, 25281490, 28933030, 32097528, 31337854, 38397245, 29158550, 35172867). The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is most likely haploinsufficiency. This gene-disease relationship does not have supporting experimental evidence. In summary, there is definitive evidence supporting the relationship between *ZMYND11* and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on March 28, 2024 (SOP 10).

intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014486

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 30AD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25217958

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZMYND11 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 313

Intellectual developmental disorder, autosomal dominant 30, with speech delay and behavioral abnormalitiesTotal: 92

Inborn genetic diseasesTotal: 66

not specifiedTotal: 26

ZMYND11-related disorderTotal: 19

See casesTotal: 3

Neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001370100.5. 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	49 clinvar	1 clinvar	53
missense	1 clinvar	21 clinvar	165 clinvar	17 clinvar	10 clinvar	214
nonsense	12 clinvar	10 clinvar	1 clinvar		1 clinvar	24
start loss						0
frameshift	26 clinvar	12 clinvar	4 clinvar		1 clinvar	43
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	3 clinvar			10
Total	41	48	176	66	13	344

Highest pathogenic variant AF is 0.0000020571927

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 202 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001370100.5	RefSeq	NP_001357029.1	14	MANE Select
ENST00000381604.9	Ensembl	ENSP00000371017.6	14	MANE Select
NM_001202464.3	RefSeq	NP_001189393.1	13	Standard
NM_001202465.3	RefSeq	NP_001189394.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of toll-like receptor signaling pathway

Biological Process

chromatin organization
cell cycle
cell population proliferation
viral process
regulation of transcription elongation from RNA polymerase II promoter

Molecular Function

double-stranded DNA binding
transcription corepressor activity
protein binding
zinc ion binding
methylated histone binding

Cellular Component

nucleus
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397962
Coding exons: 14
Length: 120173
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125739
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	158	355	0.446	0.0000205	4043
Missense (PolyPhen)		36	163	0.22085		1863
Synonymous	-0.411	122	116	1.05	0.00000657	1014
Loss of Function	5.68	1	39.6	0.0253	0.00000230	432

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and regulates RNA polymerase II elongation. Does not bind other histone H3 subtypes (H3.1 or H3.2) (By similarity). Colocalizes with highly expressed genes and functions as a transcription corepressor by modulating RNA polymerase II at the elongation stage. Binds non- specifically to dsDNA (PubMed:24675531). Acts as a tumor- suppressor by repressing a transcriptional program essential for tumor cell growth. {ECO:0000250|UniProtKB:Q8R5C8, ECO:0000269|PubMed:10734313, ECO:0000269|PubMed:16565076, ECO:0000269|PubMed:24675531}.;
Disease: DISEASE: Note=A chromosomal aberration involving ZMYND11 is a cause of acute poorly differentiated myeloid leukemia. Translocation (10;17)(p15;q21) with MBTD1. {ECO:0000269|PubMed:23915195}.; DISEASE: Mental retardation, autosomal dominant 30 (MRD30) [MIM:616083]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD30 patients manifest mild intellectual disability and subtle facial dysmorphisms, including hypertelorism, ptosis, and a wide mouth. {ECO:0000269|PubMed:25217958}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.122
RVIS EVS: -0.49
RVIS percentile EVS: 22.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

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