MADD

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

Basic information

Region (hg38): 11:47269160-47330031

Links

ENSG00000110514 ∙ NCBI:8567 ∙ OMIM:603584 ∙ HGNC:6766 ∙ Uniprot:Q8WXG6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (Strong), mode of inheritance: AR
• syndromic intellectual disability (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental delay with endocrine, exocrine, autonomic, and hematologic abnormalities (DEEAH) syndrome	AR	Endocrine	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	Craniofacial; Endocrine; Hematologic; Musculoskeletal; Neurologic	28940097; 32761064

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MADD gene.

• not provided (67 variants)
• Inborn genetic diseases (67 variants)
• Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (9 variants)
• Deeah syndrome (8 variants)
• MADD-related condition (7 variants)
• Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia;Deeah syndrome (5 variants)
• Deeah syndrome;Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (2 variants)
• not specified (2 variants)
• Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MADD gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	10	3	15
missense			102	2	5	109
nonsense	3	6	1			10
start loss						0
frameshift	3	1				4
inframe indel						0
splice donor/acceptor (+/-2bp)	1	2	1			4
splice region			1		2	3
non coding			1	1		2
Total	7	9	107	13	8

Highest pathogenic variant AF is 0.0000263

Variants in MADD

This is a list of pathogenic ClinVar variants found in the MADD region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-47273960-G-T		Inborn genetic diseases	Uncertain significance (Sep 14, 2022)
11-47274561-A-G		Deeah syndrome	Likely pathogenic (Mar 26, 2024)
11-47274581-C-A		Inborn genetic diseases	Uncertain significance (Apr 18, 2023)
11-47274594-C-A			Uncertain significance (Aug 23, 2022)
11-47274607-G-A		Inborn genetic diseases	Uncertain significance (Aug 17, 2021)
11-47274631-C-A		MADD-related disorder	Benign (Oct 28, 2019)
11-47274644-G-A			Likely benign (May 01, 2023)
11-47274699-C-T		Inborn genetic diseases	Uncertain significance (Aug 19, 2021)
11-47274733-T-C		Inborn genetic diseases	Uncertain significance (Aug 18, 2022)
11-47274768-C-T			Likely pathogenic (Jun 27, 2023)
11-47274795-C-T		Inborn genetic diseases	Uncertain significance (Jan 27, 2022)
11-47274810-C-T		Deeah syndrome	Likely pathogenic (Apr 12, 2021)
11-47274882-T-C		MADD-related disorder	Uncertain significance (Jul 12, 2023)
11-47274917-C-G		MADD-related disorder	Likely benign (Apr 01, 2023)
11-47274969-C-T		Inborn genetic diseases	Uncertain significance (May 03, 2022)
11-47274973-G-A		Inborn genetic diseases	Uncertain significance (Aug 10, 2021)
11-47274982-G-A		MADD-related disorder	Benign (Apr 26, 2019)
11-47274994-C-G		Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 04, 2022)
11-47274994-C-T			Uncertain significance (Feb 13, 2024)
11-47275008-C-T		Inborn genetic diseases	Uncertain significance (Oct 03, 2022)
11-47275009-G-A		Inborn genetic diseases	Uncertain significance (Sep 07, 2022)
11-47275068-C-T		MADD-related disorder	Likely pathogenic (Feb 13, 2023)
11-47275092-C-T		Inborn genetic diseases	Uncertain significance (Jun 09, 2022)
11-47275093-G-A		Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia	Uncertain significance (Sep 15, 2020)
11-47275140-A-G		not specified	Uncertain significance (Nov 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MADD	protein_coding	protein_coding	ENST00000311027	35	60871

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.54e-14	1.00	116195	255	9298	125748	0.0387

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.10	882	979	0.901	0.0000597	10823
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0318	0.0318
Ashkenazi Jewish	0.0339	0.0341
East Asian	0.000328	0.000326
Finnish	0.0390	0.0391
European (Non-Finnish)	0.0617	0.0616
Middle Eastern	0.000328	0.000326
South Asian	0.0141	0.0139
Other	0.0404	0.0407

dbNSFP

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}.
• Pathway: Apoptosis Modulation and Signaling;Deregulation of Rab and Rab Effector Genes in Bladder Cancer;TNF alpha Signaling Pathway;Signal Transduction;Vesicle-mediated transport;tnfr1 signaling pathway;Membrane Trafficking;ceramide signaling pathway;TNF signaling;sodd/tnfr1 signaling pathway;Rab regulation of trafficking;Death Receptor Signalling;Regulation of TNFR1 signaling;RAB GEFs exchange GTP for GDP on RABs;Caspase Cascade in Apoptosis;TNF receptor signaling pathway ;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.247

Intolerance Scores

• loftool: 0.861
• rvis_EVS: -1.96
• rvis_percentile_EVS: 1.86

Haploinsufficiency Scores

• pHI: 0.355
• hipred: Y
• hipred_score: 0.652
• ghis: 0.611

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.866

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Madd
• Phenotype: homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Gene ontology

• 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;regulation of cell cycle;execution phase of apoptosis;regulation of extrinsic apoptotic signaling pathway via death domain receptors;regulation of extrinsic apoptotic signaling pathway
• Cellular component: cytoplasm;cytosol;plasma membrane;integral component of membrane
• Molecular function: death receptor binding;protein binding;Rab guanyl-nucleotide exchange factor activity;protein kinase activator activity