MCM3AP

protein-coding

minichromosome maintenance complex component 3 associated protein, the group of Transcription and export complex 2|Lysine acetyltransferases

Gene summary

The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability. [provided by RefSeq, Jan 2014]

MANE transcript

NM_003906.5

Inheritance

ClinVar variants

P:122U:733B:522

Top phenotype

Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr21:46,235,133-46,286,297

External References & Databases

Ensembl (ENSG00000160294)

Transcript & Mutation Effects

hg38 • Region Span ~51.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0029131

Submitter: Ambry Genetics

peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029131

Submitter: PanelApp Australia

peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0029131

Submitter: ClinGen

MCM3AP was first reported in relation to autosomal recessive peripheral neuropathy disease with mild intellectual disability in 2013 (Schuurs-Hoeijmakers et al., PMID: 24123876). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did not find a difference in inheritance pattern and disease mechanism. Therefore, the associated relationship is with autosomal recessive CMT (MONDO:0018993). 18 variants (missense, frameshifts, and stop-gained) that have been reported in 12 probands in 5 publications (PMIDs: 24123876, 28969388, 28633435, 29982295, 32202298) are included in this curation. The maximum score for genetic evidence (12 pts.) was reached with a summed LOD score of 2.9. The mechanism of pathogenicity appears to be a loss-of-function given the amount of predicted or proven null variants, but more functional evidence is required to address this question. Only one functional study was used to determine MCM3AP expression in iPSC-derived neurons (PMID: 28633435). In summary, MCM3AP is DEFINITIVELY associated with autosomal recessive peripheral neuropathy with or without intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029131

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentAR

Manifestation: Musculoskeletal; 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: 24123876; 28633435; 28969388; 29982295

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCM3AP variants in ClinVar

8 Conditions Cataloged

not providedTotal: 1386

Inborn genetic diseasesTotal: 330

not specifiedTotal: 81

MCM3AP-related disorderTotal: 75

Peripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentTotal: 51

Peripheral neuropathyTotal: 2

Autism spectrum disorderTotal: 1

Congenital fibrosis of extraocular musclesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003906.5. 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		1 clinvar	4 clinvar	464 clinvar	8 clinvar	477
missense	5 clinvar	4 clinvar	715 clinvar	46 clinvar	4 clinvar	774
nonsense	23 clinvar	5 clinvar	3 clinvar			31
start loss						0
frameshift	53 clinvar	12 clinvar	3 clinvar			68
splice donor/acceptor (+/-2bp)		19 clinvar	8 clinvar			27
Total	81	41	733	510	12	1377

Highest pathogenic variant AF is 0.00019940539

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003906.5	RefSeq	NP_003897.2	28	MANE Select
ENST00000291688.6	Ensembl	ENSP00000291688.1	28	MANE Select
ENST00000397708.1	Ensembl	ENSP00000380820.1	28	Standard
ENST00000397708.2	Ensembl	ENSP00000380820.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mcm3ap	Danio rerio	Structure: head Quality: necrotic abnormal

Gene / Model

Organism

Observed Phenotype

mcm3ap

Danio rerio

Structure: head

Quality: necrotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

immune system process
mRNA export from nucleus
protein transport
poly(A)+ mRNA export from nucleus
mRNA transport

Molecular Function

nucleic acid binding
transferase activity, transferring acyl groups

Cellular Component

nucleus
nuclear pore
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397708
Coding exons: 28
Length: 51165
Individuals with no LoFs: 125633
Homozygous LoFs: 0
Heterozygous LoFs: 115
Defined: 125748
p: 0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0407	1129	1.13e+3	0.997	0.0000666	12925
Missense (PolyPhen)		365	428.62	0.85157		4924
Synonymous	-1.19	505	472	1.07	0.0000304	4028
Loss of Function	5.38	30	82.8	0.362	0.00000405	980

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00059	0.00058	rare
South Asian	0.00053	0.00052	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform GANP: Essential for the generation of high- affinity B-cells against T-cell-dependent antigens by affecting somatic hypermutation at the IgV-regions. May have stimulation- dependent DNA primase activity that would generate extra RNA primers in very rapidely proliferating cells and would support clonal expansion of differentiating B-cells (By similarity). Involved in the nuclear export of poly(A)-containing mRNAs by acting as a scaffold for the TREX-2 complex. The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. {ECO:0000250, ECO:0000269|PubMed:22307388}.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.685
RVIS EVS: -2.55
RVIS percentile EVS: 0.87

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.689

Gene Damage Prediction

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