NSD1

nuclear receptor binding SET domain protein 1, the group of PWWP domain containing|PHD finger proteins|Lysine methyltransferases

Basic information

Region (hg38): 5:177131830-177300213

Previous symbols: [ "STO" ]

Links

ENSG00000165671 ∙ NCBI:64324 ∙ OMIM:606681 ∙ HGNC:14234 ∙ Uniprot:Q96L73 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Weaver syndrome (Definitive), mode of inheritance: AD
• Beckwith-Wiedemann syndrome (Definitive), mode of inheritance: AD
• Sotos syndrome 1 (Definitive), mode of inheritance: AD
• Sotos syndrome 1 (Strong), mode of inheritance: AD
• Sotos syndrome 1 (Strong), mode of inheritance: AD
• Sotos syndrome 1 (Definitive), mode of inheritance: AD
• Sotos syndrome (Supportive), mode of inheritance: AD
• Sotos syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Sotos syndrome 1; Weaver syndrome; Beckwith-Wiedemann syndrome	AD	Cardiovascular; Oncologic; Renal	While only reported in the minority of individuals, individuals are at increased risk of malignancy, and recognition may allow prompt diagnosis and treatment; Surveillance for cardiac and renal complications may also be beneficial in order to allow prompt recognition and management	Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal	14148233; 4366187; 6324572; 3565472; 2319581; 1552397; 10507738; 10434127; 11146472; 11078573; 11813184; 11896389; 12464997; 12525543; 14517949; 14571271; 14997421; 15125616; 16010674; 15452385; 15362962; 15455365; 15365454; 16170239; 15942875; 15852475; 16222665; 16780628; 16329110; 17825104; 17480008; 17420391; 18304174; 19914434; 20101679; 20420030; 21677402; 21738022; 21834047; 22012791; 21342349; 20301652

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NSD1 gene.

• Sotos syndrome (278 variants)
• not provided (129 variants)
• Beckwith-Wiedemann syndrome (23 variants)
• Inborn genetic diseases (18 variants)
• Acute myeloid leukemia;Sotos syndrome (3 variants)
• See cases (3 variants)
• NSD1-related disorder (3 variants)
• Neurodevelopmental delay (2 variants)
• not specified (1 variants)
• Neurodevelopmental disorder (1 variants)
• Non-immune hydrops fetalis (1 variants)
• Intellectual disability (1 variants)
• 18 conditions (1 variants)
• Acute myeloid leukemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NSD1 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			15	189	16	220
missense	40	92	468	118	33	751
nonsense	110	14	1			125
start loss						0
frameshift	202	32	5			239
inframe indel		5	11	1		17
splice donor/acceptor (+/-2bp)	25	18	2			45
splice region	5	1	14	13		33
non coding			19	69	52	140
Total	377	161	521	377	101

Highest pathogenic variant AF is 0.00000657

Variants in NSD1

This is a list of pathogenic ClinVar variants found in the NSD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-177133264-CGG-C		Sotos syndrome	Uncertain significance (May 28, 2019)
5-177134112-T-C			Benign (May 01, 2020)
5-177134747-C-T			Likely benign (Dec 21, 2018)
5-177134981-A-G			Likely benign (Jan 13, 2019)
5-177135096-G-A		not specified • NSD1-related disorder • Sotos syndrome	Conflicting classifications of pathogenicity (Jul 15, 2021)
5-177135122-C-A		Sotos syndrome	Uncertain significance (Sep 24, 2021)
5-177135125-C-T		Inborn genetic diseases	Likely benign (Apr 07, 2023)
5-177135129-G-T		Sotos syndrome	Likely benign (Feb 11, 2022)
5-177135132-G-A		Sotos syndrome	Uncertain significance (Aug 26, 2021)
5-177135137-T-C		not specified • Sotos syndrome	Conflicting classifications of pathogenicity (Nov 03, 2021)
5-177135140-C-A		Inborn genetic diseases	Uncertain significance (Jan 10, 2023)
5-177135142-G-C			Likely benign (Sep 17, 2017)
5-177135145-G-C		NSD1-related disorder	Likely benign (Sep 04, 2019)
5-177135159-C-T		Sotos syndrome	Uncertain significance (Jun 21, 2019)
5-177135161-G-T		Sotos syndrome	Uncertain significance (Sep 02, 2021)
5-177135173-G-T		Sotos syndrome	Likely pathogenic (Aug 19, 2023)
5-177135175-C-T		not specified • Inborn genetic diseases • Sotos syndrome • NSD1-related disorder	Conflicting classifications of pathogenicity (Jun 13, 2024)
5-177135180-A-G		Inborn genetic diseases	Likely benign (Sep 20, 2023)
5-177135194-C-G		Sotos syndrome	Likely benign (Jul 30, 2022)
5-177135200-G-A		Sotos syndrome	Uncertain significance (Oct 10, 2022)
5-177135208-T-G			Uncertain significance (Apr 23, 2019)
5-177135211-A-G		Sotos syndrome	Uncertain significance (Feb 08, 2013)
5-177135216-A-G		Sotos syndrome	Uncertain significance (Aug 28, 2021)
5-177135243-C-G		Inborn genetic diseases	Uncertain significance (Feb 03, 2017)
5-177135244-T-C		Sotos syndrome	Likely benign (Sep 14, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NSD1	protein_coding	protein_coding	ENST00000439151	22	167191

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	7.31e-15	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.41	1065	1.43e+3	0.746	0.0000790	17650
Missense in Polyphen		179	418.12	0.42811		5206
Synonymous	0.0779	523	525	0.996	0.0000282	5309
Loss of Function	9.31	5	111	0.0452	0.00000678	1380

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000441	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Histone methyltransferase. Preferentially methylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4 (in vitro). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context. {ECO:0000269|PubMed:21196496}.
• Disease: DISEASE: Beckwith-Wiedemann syndrome (BWS) [MIM:130650]: A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. {ECO:0000269|PubMed:14997421}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98.; DISEASE: Note=A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product. {ECO:0000269|PubMed:15382262}.
• Pathway: Lysine degradation - Homo sapiens (human);Histone Modifications;Pathways Affected in Adenoid Cystic Carcinoma;PKMTs methylate histone lysines;Chromatin modifying enzymes;AndrogenReceptor;Lysine metabolism;Chromatin organization (Consensus)

Recessive Scores

• pRec: 0.241

Intolerance Scores

• loftool: 0.00186
• rvis_EVS: -1.55
• rvis_percentile_EVS: 3.24

Haploinsufficiency Scores

• pHI: 0.661
• hipred: N
• hipred_score: 0.471
• ghis: 0.580

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.959

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nsd1
• 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); embryo phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;regulation of histone H3-K36 methylation;regulation of transcription, DNA-templated;histone H3-K36 methylation;histone methylation;regulation of peptidyl-serine phosphorylation;histone H4-K20 methylation;positive regulation of transcription, DNA-templated;regulation of RNA polymerase II regulatory region sequence-specific DNA binding
• Cellular component: chromatin;nucleus;nucleoplasm;chromosome
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;chromatin binding;transcription coregulator activity;transcription corepressor activity;protein binding;zinc ion binding;histone-lysine N-methyltransferase activity;estrogen receptor binding;histone methyltransferase activity (H4-K20 specific);retinoic acid receptor binding;retinoid X receptor binding;thyroid hormone receptor binding;histone methyltransferase activity (H3-K36 specific);androgen receptor binding