SMS

protein-coding

spermine synthase, the group of Seven-beta-strand methyltransferase motif containing

Gene summary

This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Previous symbols:

MANE transcript

NM_004595.5

Inheritance

ClinVar variants

P:36U:149B:42

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson type

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:21,940,709-21,994,837

External References & Databases

Ensembl (ENSG00000102172)

Transcript & Mutation Effects

hg38 • Region Span ~54.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010664

Submitter: ClinGen

*SMS* is located on chromosome Xp22.11 and encodes spermine synthase, an enzyme involved in the synthesis of the polyamine spermine. *SMS* was first reported in relation to syndromic X-linked intellectual disability Snyder type in 2003 (Cason et al., PMID: 14508504). In affected males, the disorder is characterized by developmental delay, intellectual disability, speech abnormalities, facial dysmorphism, asthenic build, ambulation abnormalities, progressive kyphoscoliosis, early-onset osteoporosis, and seizures. Female carriers are unaffected. Nine unique variants (missense, out-of-frame-splice) that have been reported in 10 probands in 9 publications (PMIDs: 14508504, 18550699, 19206178, 22612257, 23696453, 25888122, 26174906, 26350204, 26761001) are included in this curation. Variants in this gene segregated with disease in at least 12 additional family members. The mechanism of pathogenicity is loss of function. Variants that destabilize the dimer cause loss of the SMS protein, leading to a dearth of spermine. This has been demonstrated by animal models, functional alterations in cells, and analysis of the crystal structure of SMS. In summary, there is definitive evidence supporting the relationship between *SMS* and syndromic X-linked intellectual disability Snyder type. 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 May 16, 2018 (SOP Version 5).

intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010664

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010664

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010664

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010664

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, Snyder-Robinson typeXL

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: Musculoskeletal

Rationale: Individuals manifest with osteoporosis, and calcium supplementation (with ectopic calcification monitoring) and awareness of fracture risk may be beneficial

Comments: As with other disorders that manifest with seizures, maximal seizure control is beneficial

Refs: 5823961; 14508504; 18550699; 19206178; 19277733; 21318891; 22612257; 23696453; 23805436

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMS variants in ClinVar

9 Conditions Cataloged

not providedTotal: 113

Syndromic X-linked intellectual disability Snyder typeTotal: 44

Inborn genetic diseasesTotal: 42

not specifiedTotal: 31

SMS-related disorderTotal: 23

Intellectual disabilityTotal: 2

History of neurodevelopmental disorderTotal: 1

Smith-Magenis syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004595.5. 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			11 clinvar	35 clinvar	2 clinvar	48
missense	9 clinvar	20 clinvar	113 clinvar	4 clinvar	1 clinvar	147
nonsense		2 clinvar	3 clinvar			5
start loss			2 clinvar			2
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)		4 clinvar	18 clinvar			22
Total	10	26	149	39	3	227

Highest pathogenic variant AF is 0.000008914802

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004595.5	RefSeq	NP_004586.2	11	MANE Select
ENST00000404933.7	Ensembl	ENSP00000385746.2	11	MANE Select
NM_001258423.2	RefSeq	NP_001245352.1	9	Standard
ENST00000379404.5	Ensembl	ENSP00000368714.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sms	Danio rerio	Structure: spermine biosynthetic process Quality: decreased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

sms

Danio rerio

Structure: spermine biosynthetic process

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
beta-Alanine metabolism - Homo sapiens (human)
Glutathione metabolism - Homo sapiens (human)
Cysteine and methionine metabolism - Homo sapiens (human)
Spermidine and Spermine Biosynthesis

Biological Process

methionine metabolic process
polyamine metabolic process
spermine biosynthetic process

Molecular Function

spermine synthase activity

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404933
Coding exons: 11
Length: 67108
Individuals with no LoFs: 122687
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 122688
p: 0.00000408

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.32	66	144	0.457	0.0000113	2405
Missense (PolyPhen)		4	36.234	0.11039		678
Synonymous	-0.289	62	59.2	1.05	0.00000519	667
Loss of Function	3.42	1	15.5	0.0643	0.00000121	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000090	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM).;
Disease: DISEASE: X-linked syndromic mental retardation Snyder-Robinson type (MRXSSR) [MIM:309583]: Characterized by moderate intellectual deficit, hypotonia, an unsteady gait, osteoporosis, kyphoscoliosis and facial asymmetry. Transmission is X-linked recessive. {ECO:0000269|PubMed:14508504, ECO:0000269|PubMed:18550699, ECO:0000269|PubMed:19206178, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23696453, ECO:0000269|PubMed:23897707}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.0880
RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.943

Gene Damage Prediction

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