NSD1

protein-coding

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

Gene summary

This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Sep 2018]

Previous symbols:

MANE transcript

NM_022455.5

Inheritance

ClinVar variants

P:781U:1013B:811

Top phenotype

Sotos syndrome 1; Weaver syndrome; Beckwith-Wiedemann syndrome

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr5:177,131,830-177,300,213

External References & Databases

Ensembl (ENSG00000165671)

Transcript & Mutation Effects

hg38 • Region Span ~168.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Sotos syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007299

Submitter: Labcorp Genetics (formerly Invitae)

Sotos syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019349

Submitter: ClinGen

*NSD1* encodes a histone methyltransferase. *NSD1* was first reported in relation to autosomal dominant Sotos syndrome in 2002 (Kurotaki et al., PMID: 11896389). Sotos syndrome is characterized by overgrowth, distinctive facial features, and intellectual disability. Other major features include autism spectrum disorder, advanced bone age, cardiac and renal anomalies, brain neuroimaging abnormalities, and seizures. 5q35 microdeletions that encompass the entire *NSD1* gene are a common cause of Sotos syndrome and tend to be associated with more severe learning disability than intragenic pathogenic variants (PMID: 15942875). Over 300 unique pathogenic variants (including missense, frameshift, nonsense, splice, and large deletions) have been reported in ClinVar. Eight truncating variants (frameshift, nonsense, and splice) that have been reported in nine probands in two publications (PMIDs: 12464997, 12525543) are included in this curation. Variants usually occur *de novo* but can be inherited (e.g., PMID: 12525543). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is haploinsufficiency (PMID: 11896389). This gene-disease relationship is also supported by a mouse model and *in vitro* functional studies. In summary, there is definitive evidence supporting the relationship between *NSD1* and autosomal dominant Sotos syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 26, 2018 (SOP Version 6).

Sotos syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007299

Submitter: Genomics England PanelApp

Sotos syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019349

Submitter: G2P

Sotos syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007299

Submitter: Ambry Genetics

Sotos syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019349

Submitter: PanelApp Australia

Beckwith-Wiedemann syndrome due to NSD1 mutationDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016547

Submitter: G2P

Sotos syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019349

Submitter: Orphanet

Clinical Genomic Database (CGD)

Sotos syndrome 1; Weaver syndrome; Beckwith-Wiedemann syndromeAD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Oncologic; Renal

Rationale: 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

Refs: 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

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSD1 variants in ClinVar

35 Conditions Cataloged

not providedTotal: 1919

Sotos syndromeTotal: 932

Inborn genetic diseasesTotal: 444

not specifiedTotal: 289

NSD1-related disorderTotal: 213

Beckwith-Wiedemann syndromeTotal: 32

Acute myeloid leukemiaTotal: 8

See casesTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022455.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			21 clinvar	388 clinvar	18 clinvar	427
missense	54 clinvar	152 clinvar	960 clinvar	364 clinvar	40 clinvar	1570
nonsense	130 clinvar	31 clinvar	6 clinvar			167
start loss						0
frameshift	267 clinvar	85 clinvar	12 clinvar	1 clinvar		365
splice donor/acceptor (+/-2bp)	32 clinvar	30 clinvar	14 clinvar			76
Total	483	298	1013	753	58	2605

Highest pathogenic variant AF is 0.0000065720296

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022455.5	RefSeq	NP_071900.2	22	MANE Select
ENST00000439151.7	Ensembl	ENSP00000395929.2	22	MANE Select
NM_001365684.2	RefSeq	NP_001352613.2	22	Standard
NM_001409301.1	RefSeq	NP_001396230.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Pathways Affected in Adenoid Cystic Carcinoma
PKMTs methylate histone lysines
Chromatin modifying enzymes

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

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
chromatin binding
transcription coregulator activity
transcription corepressor activity
protein binding

Cellular Component

chromatin
nucleus
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000439151
Coding exons: 22
Length: 167191
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.41	1065	1.43e+3	0.746	0.0000790	17650
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.241

Intolerance Scores

LoFtool: 0.00186
RVIS EVS: -1.55
RVIS percentile EVS: 3.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.959

Gene Damage Prediction

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