DYRK1A

protein-coding

dual specificity tyrosine phosphorylation regulated kinase 1A

Gene summary

This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of Drosophila mnb (minibrain) gene and rat Dyrk gene. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region. These variants encode at least five different isoforms. [provided by RefSeq, Jul 2008]

Previous symbols:

DYRK1
DYRK
MNBH

MANE transcript

NM_001347721.2

Inheritance

ClinVar variants

P:274U:323B:346

Top phenotype

Intellectual developmental disorder, autosomal dominant 7

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr21:37,365,573-37,526,358

External References & Databases

Ensembl (ENSG00000157540)

Transcript & Mutation Effects

hg38 • Region Span ~160.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

DYRK1A-related intellectual disability syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013578

Submitter: Labcorp Genetics (formerly Invitae)

DYRK1A-related intellectual disability syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013578

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The relationship between DYRK1A and complex neurodevelopmental disorder (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10/05/2019. Variants in DYRK1A were first reported in humans with this disease as early as 2011 (van Bon et al., PMID: 21294719). Numerous unique variants in DYRK1A (e.g. nonsense, frameshift, splice site and missense) have been reported in humans, and most variants occur de novo. The mechanism for disease is haploinsufficiency. Loss of DYRK1A results in a recognizable phenotype, including microcephaly and restricted growth, intellectual disability, delayed or absent speech, autism spectrum disorder or autistic behavior, gait disturbance, seizures, and dysmorphic facial features. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 13 probands in 10 publications (21294719, 23099646, 23160955, 25167861, 25156961, 25641759, 25920557, 25944381, 26922654, 25707398). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Experimental evidence: 4.5 POINTS. This gene-disease association is supported by expression studies, animal models, and functional studies in non-patient cells. In summary, DYRK1A is definitely associated with autosomal dominant complex neurodevelopmental disorder.

DYRK1A-related intellectual disability syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013578

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 7AD

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: 18405873; 21294719; 23099646; 23160955

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to DYRK1A variants in ClinVar

21 Conditions Cataloged

DYRK1A-related intellectual disability syndromeTotal: 869

not providedTotal: 327

Inborn genetic diseasesTotal: 134

not specifiedTotal: 84

Intellectual disabilityTotal: 36

DYRK1A-related disorderTotal: 23

Complex neurodevelopmental disorderTotal: 18

MicrocephalyTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001347721.2. 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			6 clinvar	214 clinvar	2 clinvar	222
missense	13 clinvar	35 clinvar	312 clinvar	96 clinvar	34 clinvar	490
nonsense	49 clinvar	12 clinvar				61
start loss	1 clinvar					1
frameshift	114 clinvar	21 clinvar	4 clinvar			139
splice donor/acceptor (+/-2bp)	15 clinvar	14 clinvar	1 clinvar			30
Total	192	82	323	310	36	943

Highest pathogenic variant AF is 0.00015748937

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001347721.2	RefSeq	NP_001334650.1	11	MANE Select
ENST00000647188.2	Ensembl	ENSP00000494572.1	11	MANE Select
NM_001347722.2	RefSeq	NP_001334651.1	11	Standard
NM_001347723.2	RefSeq	NP_001334652.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HH-Ncore
T-Cell Receptor and Co-stimulatory Signaling
Hedgehog
TCR
G0 and Early G1

Biological Process

regulation of alternative mRNA splicing, via spliceosome
protein phosphorylation
nervous system development
circadian rhythm
viral process

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein serine/threonine/tyrosine kinase activity
protein tyrosine kinase activity
non-membrane spanning protein tyrosine kinase activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytoskeleton
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398960
Coding exons: 11
Length: 151662
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125712
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.34	246	444	0.554	0.0000250	5048
Missense (PolyPhen)		39	145.48	0.26808		1677
Synonymous	-1.48	179	156	1.15	0.00000878	1454
Loss of Function	5.11	3	36.2	0.0828	0.00000202	401

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
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)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Exhibits a substrate preference for proline at position P+1 and arginine at position P- 3. Has pro-survival function and negatively regulates the apoptotic process. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits TP53 activity and apoptosis (By similarity). {ECO:0000250|UniProtKB:Q61214, ECO:0000250|UniProtKB:Q9NR20, ECO:0000269|PubMed:20981014, ECO:0000269|PubMed:21127067, ECO:0000269|PubMed:23665168, ECO:0000269|PubMed:8769099}.;
Disease: DISEASE: Mental retardation, autosomal dominant 7 (MRD7) [MIM:614104]: A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21294719, ECO:0000269|PubMed:23160955}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.316

Intolerance Scores

LoFtool: 0.220
RVIS EVS: -0.42
RVIS percentile EVS: 25.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.985

Gene Damage Prediction

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