NFIX

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

Basic information

Region (hg38): 19:12995474-13098796

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
• Malan overgrowth 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.

• not provided (125 variants)
• Marshall-Smith syndrome;Malan overgrowth syndrome (70 variants)
• Malan overgrowth syndrome (34 variants)
• Malan overgrowth syndrome;Marshall-Smith syndrome (33 variants)
• Marshall-Smith syndrome (26 variants)
• Inborn genetic diseases (19 variants)
• not specified (6 variants)
• See cases (3 variants)
• Intellectual disability (3 variants)
• NFIX-related condition (3 variants)
• Marfanoid habitus and intellectual disability (2 variants)
• 15 conditions (1 variants)
• Neurodevelopmental disorder (1 variants)
• - (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.

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			1	40	4	45
missense	7	20	50	3	1	81
nonsense	19	4				23
start loss			1			1
frameshift	38	11				49
inframe indel		1	5			6
splice donor/acceptor (+/-2bp)	3	5	1			9
splice region			6	2		8
non coding			10	34	17	61
Total	67	41	68	77	22

Variants in NFIX

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

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

Position	Type	Phenotype	Significance	ClinVar
19-12995838-A-G			Uncertain significance (Nov 19, 2019)
19-12995863-A-C		Malan overgrowth syndrome;Marshall-Smith syndrome	Uncertain significance (May 20, 2021)
19-12995863-A-G		Inborn genetic diseases	Uncertain significance (Feb 28, 2023)
19-12995977-C-T			Likely benign (Jun 16, 2018)
19-12996142-CGT-C			Benign (Sep 02, 2019)
19-12996142-CGTGT-C			Benign (Jan 18, 2020)
19-12996142-C-CGT			Benign (Dec 07, 2020)
19-13023630-CT-C			Likely benign (Aug 20, 2019)
19-13023630-CTTTTTTTT-C			Benign (Sep 02, 2019)
19-13023687-A-T			Likely benign (Jun 16, 2018)
19-13024113-CA-C			Benign (Aug 09, 2019)
19-13024113-C-CA		Marshall-Smith syndrome	Benign/Likely benign (Nov 01, 2019)
19-13024219-G-A			Likely benign (Sep 05, 2018)
19-13024383-T-C			Benign (Jun 16, 2018)
19-13024520-G-C			Likely benign (Apr 01, 2023)
19-13024630-G-C			Uncertain significance (Jul 01, 2018)
19-13024645-A-T			Likely benign (Dec 27, 2018)
19-13024651-G-A		Marshall-Smith syndrome;Malan overgrowth syndrome	Likely benign (Oct 23, 2023)
19-13024653-G-T		Marshall-Smith syndrome;Malan overgrowth syndrome	Likely benign (Aug 10, 2023)
19-13024666-G-A		Marshall-Smith syndrome;Malan overgrowth syndrome	Likely benign (May 25, 2022)
19-13024666-G-GGGGATACC			Uncertain significance (Oct 24, 2022)
19-13024680-C-CGT		Marshall-Smith syndrome;Malan overgrowth syndrome	Uncertain significance (Sep 03, 2023)
19-13024694-C-T		Marshall-Smith syndrome;Malan overgrowth syndrome	Likely benign (Oct 03, 2023)
19-13024695-G-A		Malan overgrowth syndrome;Marshall-Smith syndrome	Benign (Jan 28, 2024)
19-13024699-A-G		Marshall-Smith syndrome;Malan overgrowth syndrome	Likely benign (Jun 15, 2022)

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