NFIX

nuclear factor I X, the group of Nuclear factor I family

Basic information

Region (hg38): 19:12995475-13098796

Links

ENSG00000008441 ∙ NCBI:4784 ∙ OMIM:164005 ∙ HGNC:7788 ∙ Uniprot:Q14938 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Malan overgrowth syndrome (Definitive), mode of inheritance: AD
• Marshall-Smith syndrome (Definitive), mode of inheritance: AD
• Marshall-Smith syndrome (Definitive), mode of inheritance: AD
• Marshall-Smith syndrome (Moderate), mode of inheritance: AD
• Malan overgrowth syndrome (Definitive), mode of inheritance: AD
• Marshall-Smith syndrome (Supportive), mode of inheritance: AD
• Malan overgrowth syndrome (Supportive), mode of inheritance: AD
• Marshall-Smith syndrome (Strong), mode of inheritance: AD
• Malan overgrowth syndrome (Strong), mode of inheritance: AD
• Marshall-Smith syndrome (Definitive), mode of inheritance: AD
• Malan overgrowth syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Marshall-Smith syndrome; Malan overgrowth syndrome (Sotos syndrome 2)	AD	General	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	Craniofacial; Musculoskeletal; Neurologic; Pulmonary	20673863; 22301465; 22982744

ClinVar

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

• Malan_overgrowth_syndrome (251 variants)
• Marshall-Smith_syndrome (243 variants)
• not_provided (149 variants)
• Inborn_genetic_diseases (34 variants)
• NFIX-related_disorder (13 variants)
• not_specified (12 variants)
• Intellectual_disability (4 variants)
• See_cases (3 variants)
• Marfanoid_habitus_and_intellectual_disability (2 variants)
• Blue_sclerae (1 variants)
• Proximal_placement_of_thumb (1 variants)
• Long_toe (1 variants)
• High,_narrow_palate (1 variants)
• Neurodevelopmental_disorder (1 variants)
• Congenital_laryngomalacia (1 variants)
• Strabismus (1 variants)
• Pointed_chin (1 variants)
• Global_developmental_delay (1 variants)
• Megalocornea (1 variants)
• Proptosis (1 variants)
• Short_nose (1 variants)
• Hypoplasia_of_the_corpus_callosum (1 variants)
• Long_fingers (1 variants)
• Distal_ulnar_hypoplasia (1 variants)
• Midface_retrusion (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFIX gene is commonly pathogenic or not. These statistics are base on transcript: NM_001365902.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	68	8	79
missense	12	32	91	12		147
nonsense	23	6				29
start loss			1			1
frameshift	59	13	1			73
splice donor/acceptor (+/-2bp)	7	6	2			15
Total	101	57	98	80	8

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFIX	protein_coding	protein_coding	ENST00000397661	9	103189

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000969	124614	0	4	124618	0.0000160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.08	78	265	0.295	0.0000171	2831
Missense in Polyphen		27	124.81	0.21633		1339
Synonymous	0.963	106	119	0.888	0.00000809	909
Loss of Function	4.15	0	20.1	0.00	9.65e-7	241

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000885	0.00000885
Middle Eastern	0.00	0.00
South Asian	0.0000654	0.0000654
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Recognizes and binds the palindromic sequence 5'- TTGGCNNNNNGCCAA-3' present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.
• Disease: DISEASE: Sotos syndrome 2 (SOTOS2) [MIM:614753]: A form of Sotos syndrome, a childhood overgrowth syndrome characterized by prenatal and postnatal overgrowth, developmental delay, mental retardation, advanced bone age, and abnormal craniofacial morphology. SOTOS2 patients have macrocephaly, long narrow face, high forehead, slender habitus, scoliosis, and unusual behavior characterized especially by anxiety. {ECO:0000269|PubMed:20673863, ECO:0000269|PubMed:22301465, ECO:0000269|PubMed:26193383, ECO:0000269|PubMed:26200704}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Marshall-Smith syndrome (MRSHSS) [MIM:602535]: A distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. Additional skeletal findings include long and thin tubular bones, broad middle phalanges with relatively narrow distal phalanges, and scoliosis. {ECO:0000269|PubMed:20673863, ECO:0000269|PubMed:26200704}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Oxidative Stress;Gene expression (Transcription);RNA Polymerase III Transcription Termination;RNA Polymerase III Abortive And Retractive Initiation;RNA Polymerase III Transcription (Consensus)

Recessive Scores

• pRec: 0.0938

Intolerance Scores

• loftool: 0.0911
• rvis_EVS: -0.27
• rvis_percentile_EVS: 33.97

Haploinsufficiency Scores

• pHI: 0.352
• hipred: Y
• hipred_score: 0.715
• ghis: 0.635

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.972

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low

Mouse Genome Informatics

• Gene name: Nfix
• Phenotype: skeleton phenotype; vision/eye phenotype; hearing/vestibular/ear 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); digestive/alimentary 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); normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); craniofacial phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: nfixa
• Affected structure: muscle precursor cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;DNA replication;transcription by RNA polymerase II;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleus
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding