DIAPH1

diaphanous related formin 1, the group of Formins|Armadillo like helical domain containing

Basic information

Region (hg38): 5:141515015-141619055

Previous symbols: [ "DFNA1" ]

Links

ENSG00000131504 ∙ NCBI:1729 ∙ OMIM:602121 ∙ HGNC:2876 ∙ Uniprot:O60610 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant nonsyndromic hearing loss 1 (Strong), mode of inheritance: AD
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (Supportive), mode of inheritance: AR
• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (Supportive), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 1 (Strong), mode of inheritance: AD
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (Strong), mode of inheritance: AR
• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal dominant 1, with or without thrombocytopenia	AD	Audiologic/Otolaryngologic	Onset has been described as prelingual in some individuals, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	7211837; 1350680; 9360932; 22938506; 24781755; 26463574; 26912466; 28815995

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DIAPH1 gene.

• Autosomal dominant nonsyndromic hearing loss 1;Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (616 variants)
• Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome;Autosomal dominant nonsyndromic hearing loss 1 (338 variants)
• not provided (213 variants)
• Autosomal dominant nonsyndromic hearing loss 1 (120 variants)
• not specified (73 variants)
• Inborn genetic diseases (50 variants)
• Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (9 variants)
• Nonsyndromic Hearing Loss, Mixed (8 variants)
• DIAPH1-related condition (7 variants)
• Hearing impairment (3 variants)
• Vascular dementia (1 variants)
• Beta-D-mannosidosis (1 variants)
• Microcephaly (1 variants)
• See cases (1 variants)
• Pendred syndrome (1 variants)
• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (1 variants)
• Global developmental delay;Failure to thrive;Microcephaly;Epilepsy (1 variants)
• Rare genetic deafness (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DIAPH1 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			12	215	4	231
missense			495	16	3	514
nonsense	11		3			14
start loss						0
frameshift	10	5	2			17
inframe indel			24	3	1	28
splice donor/acceptor (+/-2bp)	1	6		1		8
splice region			27	42	7	76
non coding			31	187	32	250
Total	22	11	567	422	40

Highest pathogenic variant AF is 0.000131

Variants in DIAPH1

This is a list of pathogenic ClinVar variants found in the DIAPH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-141515084-C-CAG		Nonsyndromic Hearing Loss, Mixed	Conflicting classifications of pathogenicity (Feb 01, 2023)
5-141515132-CCTCT-C		Nonsyndromic Hearing Loss, Mixed	Uncertain significance (Jun 14, 2016)
5-141515197-G-C		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515214-C-G		Autosomal dominant nonsyndromic hearing loss 1	Likely benign (Jan 12, 2018)
5-141515223-GGGA-G		Nonsyndromic Hearing Loss, Mixed	Likely benign (Jun 14, 2016)
5-141515244-G-A		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 12, 2018)
5-141515254-C-T		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 13, 2018)
5-141515294-G-A		Autosomal dominant nonsyndromic hearing loss 1	Likely benign (Jan 12, 2018)
5-141515307-T-C		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515318-G-A		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 12, 2018)
5-141515407-A-C		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515456-G-A		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515487-A-G		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 13, 2018)
5-141515504-G-C		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 13, 2018)
5-141515514-G-A		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515529-G-C		Autosomal dominant nonsyndromic hearing loss 1	Likely benign (Jan 12, 2018)
5-141515542-T-A		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515547-T-C		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 12, 2018)
5-141515810-C-T		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 13, 2018)
5-141515845-A-G		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)
5-141515918-A-T		Autosomal dominant nonsyndromic hearing loss 1	Benign (Jan 12, 2018)
5-141515918-A-AT		Nonsyndromic Hearing Loss, Mixed	Uncertain significance (Jun 14, 2016)
5-141515981-C-T		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 12, 2018)
5-141515984-C-T		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 12, 2018)
5-141516040-T-G		Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DIAPH1	protein_coding	protein_coding	ENST00000398557	28	104040

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.915	0.0849	124739	0	58	124797	0.000232

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.65	535	654	0.818	0.0000358	8317
Missense in Polyphen		81	118.53	0.68338		1529
Synonymous	-0.651	249	236	1.05	0.0000121	2465
Loss of Function	5.80	12	60.8	0.197	0.00000354	765

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000406	0.000406
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000584	0.0000556
Finnish	0.00139	0.00139
European (Non-Finnish)	0.0000972	0.0000971
Middle Eastern	0.0000584	0.0000556
South Asian	0.0000327	0.0000327
Other	0.000165	0.000165

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers (By similarity). Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization (By similarity). Required for cytokinesis, and transcriptional activation of the serum response factor (By similarity). DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics (By similarity). Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane (By similarity). In hear cells, it may play a role in the regulation of actin polymerization in hair cells (PubMed:20937854, PubMed:21834987, PubMed:26912466). The MEMO1- RHOA-DIAPH1 signaling pathway plays an important role in ERBB2- dependent stabilization of microtubules at the cell cortex (PubMed:20937854, PubMed:21834987). It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity (PubMed:20937854, PubMed:21834987). In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854, PubMed:21834987). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape (PubMed:20937854, PubMed:21834987). Plays a role in brain development (PubMed:24781755). Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity (By similarity). {ECO:0000250|UniProtKB:O08808, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21834987, ECO:0000269|PubMed:24781755, ECO:0000269|PubMed:26912466}.
• Disease: DISEASE: Deafness, autosomal dominant, 1 (DFNA1) [MIM:124900]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. Patients may have mild thrombocytopenia and enlarged platelets, although most of DFNA1 affected individuals do not have significant bleeding tendencies. {ECO:0000269|PubMed:22938506, ECO:0000269|PubMed:26912466, ECO:0000269|PubMed:27808407, ECO:0000269|PubMed:9360932}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Seizures, cortical blindness, and microcephaly syndrome (SCBMS) [MIM:616632]: A severe autosomal recessive neurodevelopmental disorder characterized by microcephaly, early- onset seizures, severely delayed psychomotor development, short stature, and cortical blindness. {ECO:0000269|PubMed:24781755, ECO:0000269|PubMed:26463574}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Focal adhesion - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Shigellosis - Homo sapiens (human);Regulation of Microtubule Cytoskeleton;AGE-RAGE pathway;Focal Adhesion;Type 2 papillary renal cell carcinoma;Regulation of Actin Cytoskeleton;G13 Signaling Pathway;Neutrophil degranulation;Signal Transduction;erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;rho cell motility signaling pathway;TCR;Innate Immune System;Immune System;RHO GTPases Activate Formins;RHO GTPase Effectors;Signaling by Rho GTPases;role of mal in rho-mediated activation of srf;Signaling by ERBB2;ERBB2 Regulates Cell Motility;Integrin-linked kinase signaling;Signaling by Receptor Tyrosine Kinases;Stabilization and expansion of the E-cadherin adherens junction;RhoA signaling pathway (Consensus)

Recessive Scores

• pRec: 0.164

Intolerance Scores

• loftool: 0.270
• rvis_EVS: -1.24
• rvis_percentile_EVS: 5.46

Haploinsufficiency Scores

• pHI: 0.498
• hipred: Y
• hipred_score: 0.590
• ghis: 0.514

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.924

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Diaph1
• Phenotype: 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); hematopoietic system phenotype; skeleton phenotype; immune system phenotype; 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); 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); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype

Gene ontology

• Biological process: cytoskeleton organization;sensory perception of sound;regulation of cell shape;actin cytoskeleton organization;actin filament polymerization;positive regulation of cell migration;regulation of microtubule-based process;protein localization to microtubule;neutrophil degranulation;regulation of release of sequestered calcium ion into cytosol;regulation of cytoskeleton organization;cellular response to histamine;regulation of cell motility
• Cellular component: nucleus;cytoplasm;microtubule organizing center;cytosol;plasma membrane;secretory granule membrane;ruffle membrane;mitotic spindle;ficolin-1-rich granule membrane
• Molecular function: RNA binding;actin binding;signaling receptor binding;protein binding;Rho GTPase binding;ion channel binding