MAD1L1

protein-coding

mitotic arrest deficient 1 like 1, the group of MicroRNA protein coding host genes

Gene summary

MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MANE transcript

NM_001013836.2

Inheritance

ClinVar variants

P:8U:135B:15

Top phenotype

Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr7:1,815,793-2,233,243

External References & Databases

Ensembl (ENSG00000002822)

Transcript & Mutation Effects

hg38 • Region Span ~417.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial prostate carcinomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0023122

Submitter: Labcorp Genetics (formerly Invitae)

mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predispositionLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859346

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predispositionAR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic

Intervention: Oncologic

Rationale: The condition can involve increased risk of a variaty of neoplasms, and awareness may allow early detection and management

Refs: 36322655

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAD1L1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 133

not providedTotal: 17

Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predispositionTotal: 5

Mosaic variegated aneuploidy syndrome 1Total: 2

Prostate cancerTotal: 1

Prostate cancer, somaticTotal: 1

LYMPHOMA, DIFFUSE LARGE B-CELL, SOMATICTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001013836.2. 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			3 clinvar	7 clinvar	3 clinvar	13
missense			127 clinvar	5 clinvar		132
nonsense	4 clinvar	3 clinvar				7
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	5	3	135	12	3	158

Highest pathogenic variant AF is 0.00005640962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001013836.2	RefSeq	NP_001013858.1	17	MANE Select
ENST00000265854.12	Ensembl	ENSP00000265854.7	17	MANE Select
NM_001013837.2	RefSeq	NP_001013859.1	17	Standard
NM_001304523.2	RefSeq	NP_001291452.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)
Progesterone-mediated oocyte maturation - Homo sapiens (human)
Cell Cycle
Regulation of sister chromatid separation at the metaphase-anaphase transition

Biological Process

mitotic cell cycle checkpoint
mitotic spindle assembly checkpoint
negative regulation of T cell proliferation
thymus development
cell division

Molecular Function

protein binding
identical protein binding
kinetochore binding

Cellular Component

kinetochore
condensed chromosome kinetochore
nuclear envelope
centrosome
spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406869
Coding exons: 17
Length: 417450
Individuals with no LoFs: 124762
Homozygous LoFs: 0
Heterozygous LoFs: 114
Defined: 124876
p: 0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0252	460	462	0.997	0.0000317	4660
Missense (PolyPhen)		136	139.42	0.97545		1508
Synonymous	-0.809	210	196	1.07	0.0000136	1373
Loss of Function	1.71	30	42.0	0.715	0.00000204	465

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00059	0.00058	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00012	0.000099	rare
East Asian	0.00045	0.00044	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00054	0.00054	rare
South Asian	0.00049	0.00049	rare
Other	0.00066	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. May recruit MAD2L1 to unattached kinetochores. Has a role in the correct positioning of the septum. Required for anchoring MAD2L1 to the nuclear periphery. Binds to the TERT promoter and represses telomerase expression, possibly by interfering with MYC binding. {ECO:0000269|PubMed:10049595, ECO:0000269|PubMed:12837246, ECO:0000269|PubMed:20133940}.;
Disease: DISEASE: Note=Defects in MAD1L1 are involved in the development and/or progression of various types of cancer. {ECO:0000269|PubMed:10597320, ECO:0000269|PubMed:11423979}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.924
RVIS EVS: -1.32
RVIS percentile EVS: 4.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.850

Gene Damage Prediction

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