MADD

protein-coding

MAP kinase activating death domain, the group of DENN domain containing

Gene summary

Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mitogen-activated protein kinase (MAPK) and propagate the apoptotic signal. It is membrane-bound and expressed at a higher level in neoplastic cells than in normal cells. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001376571.1

Inheritance

AR, AD

ClinVar variants

P:42U:288B:51

Top phenotype

Developmental delay with endocrine, exocrine, autonomic, and hematologic abnormalities (DEEAH) syndrome

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr11:47,269,161-47,330,031

External References & Databases

Ensembl (ENSG00000110514)

Transcript & Mutation Effects

hg38 • Region Span ~60.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

deeah syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033561

Submitter: PanelApp Australia

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotoniaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033562

Submitter: G2P

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotoniaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033562

Submitter: Ambry Genetics

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotoniaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033562

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental delay with endocrine, exocrine, autonomic, and hematologic abnormalities (DEEAH) syndromeAR

Manifestation: Craniofacial; Endocrine; Hematologic; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: Among other findings, individuals have been described with endocrine anomalies (eg, hypoglycemia, thyroid dysfunction, growth hormone deficiency, and panhypopituitarism), and awareness may allow early diagnosis of medical management of these manifestations

Refs: 28940097; 32761064

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MADD variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 218

not providedTotal: 117

MADD-related disorderTotal: 39

Deeah syndromeTotal: 29

Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotoniaTotal: 26

not specifiedTotal: 5

Autosomal recessive MADD-related disordersTotal: 4

Multiple acyl-CoA dehydrogenase deficiency, severe neonatal typeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001376571.1. 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	7 clinvar	35 clinvar	3 clinvar	46
missense	3 clinvar	2 clinvar	268 clinvar	10 clinvar	3 clinvar	286
nonsense	3 clinvar	9 clinvar	3 clinvar			15
start loss						0
frameshift	5 clinvar	12 clinvar				17
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	10 clinvar			17
Total	13	29	288	45	6	381

Highest pathogenic variant AF is 0.00013258787

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 295 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001376571.1	RefSeq	NP_001363500.1	36	MANE Select
ENST00000706887.1	Ensembl	ENSP00000516604.1	36	MANE Select
NM_001135943.2	RefSeq	NP_001129415.1	32	Standard
NM_001135944.2	RefSeq	NP_001129416.1	32	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis Modulation and Signaling
Deregulation of Rab and Rab Effector Genes in Bladder Cancer
TNF alpha Signaling Pathway
Signal Transduction
Vesicle-mediated transport

Biological Process

activation of MAPK activity
cell surface receptor signaling pathway
regulation of tumor necrosis factor-mediated signaling pathway
regulation of Rab protein signal transduction
regulation of apoptotic process

Molecular Function

death receptor binding
protein binding
Rab guanyl-nucleotide exchange factor activity
protein kinase activator activity

Cellular Component

cytoplasm
cytosol
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311027
Coding exons: 35
Length: 60871
Individuals with no LoFs: 116195
Homozygous LoFs: 255
Heterozygous LoFs: 9298
Defined: 125748
p: 0.0387

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.10	882	979	0.901	0.0000597	10823
Missense (PolyPhen)		305	418.81	0.72825		4603
Synonymous	-0.392	390	380	1.03	0.0000230	3260
Loss of Function	4.87	39	88.5	0.441	0.00000523	945

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0093	0.0093	notable
Latino/Admixed American	0.022	0.022	notable
Ashkenazi Jewish	0.034	0.034	notable
East Asian	0.00033	0.00033	rare
Finnish	0.039	0.039	notable
European (Non-Finnish)	0.062	0.062	notable
South Asian	0.014	0.014	notable
Other	0.040	0.041	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a significant role in regulating cell proliferation, survival and death through alternative mRNA splicing. Isoform 5 shows increased cell proliferation and isoform 2 shows decreased. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms. Component of the TNFRSF1A signaling complex: MADD links TNFRSF1A with MAP kinase activation. Plays an important regulatory role in physiological cell death (TNF-alpha-induced, caspase-mediated apoptosis); isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant and isoform 3 and isoform 4 have no effect. {ECO:0000269|PubMed:11577081, ECO:0000269|PubMed:14716293, ECO:0000269|PubMed:14735464, ECO:0000269|PubMed:15007167, ECO:0000269|PubMed:20937701, ECO:0000269|PubMed:9115275}.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.861
RVIS EVS: -1.96
RVIS percentile EVS: 1.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.866

Gene Damage Prediction

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