SAMD9

protein-coding

sterile alpha motif domain containing 9, the group of Sterile alpha motif domain containing

Gene summary

This gene encodes a sterile alpha motif domain-containing protein. The encoded protein localizes to the cytoplasm and may play a role in regulating cell proliferation and apoptosis. Mutations in this gene are the cause of normophosphatemic familial tumoral calcinosis. Alternate splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Jul 2010]

Previous symbols:

C7orf5

MANE transcript

NM_017654.4

Inheritance

AD, AR

ClinVar variants

P:48U:1912B:903

Top phenotype

Mirage syndrome; Monosomy 7 myelodysplasia and leukemia syndrome 2; Tumoral calcinosis, normophosphatemic, familial

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr7:93,099,513-93,118,023

External References & Databases

Ensembl (ENSG00000205413)

Transcript & Mutation Effects

hg38 • Region Span ~18.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SAMD9-related spectrum and myeloid neoplasm riskDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100628

Submitter: ClinGen

SAMD9 was first reported in relation to autosomal dominant SAMD9-related spectrum and myeloid neoplasm risk in 2016 (Narumi et al., PMID: 27182967). SAMD9-related spectrum and myeloid neoplasm risk is a syndromic condition characterized by myelodysplasia, adrenal hypoplasia, growth restriction, genital phenotypes, enteropathy, developmental delay, and dysmorphic features. SAMD9 has been associated with MIRAGE syndrome (OMIM 617053), Monosomy 7 myelodysplasia and leukemia syndrome 2 (OMIM 619041), and Tumoral calcinosis, familial, normophosphatemic (OMIM 610455). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, molecular mechanism and phenotypic variability. Therefore, the disease entities have been split into two disease entities by inheritance pattern. The autosomal dominant MIRAGE syndrome and monosomy 7 myelodysplasia and leukemia syndrome 2 were lumped together while the recessive tumoral calcinosis, familial, normophosphatemic was split. This curation addresses SAMD9 in relation to the SAMD9-related spectrum and myeloid neoplasm risk, which includes the autosomal dominant conditions. The spectrum can affect multiple organ systems, particularly endocrine, cardiopulmonary, genitourinary, and gastrointestinal systems, and also include immune deficiency. Sixteen unique missense variants that have been reported in at least 20 probands in 4 publications (PMIDs: 27182967, 28487541, 28346228, 30046003) are included in this curation. More genetic evidence is available in the literature, however, the maximum points for genetic evidence has been reached. The mechanism of pathogenicity appears to be gain-of-function. Of note, there have been two biallelic cases reported in the literature with some features of autosomal dominant SAMD9-related spectrum and myeloid neoplasm risk (PMIDs: 31900929, 37830462). This gene-disease relationship is also supported by experimental evidence including expression data, and functional alteration data in patient cells (PMIDs: 27182967, 2834622). In summary, there is definitive evidence supporting the relationship between SAMD9 and autosomal dominant SAMD9-related spectrum and myeloid neoplasm risk. 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 Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date December 10th, 2024 (SOP Version 11).

normophosphatemic familial tumoral calcinosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: Labcorp Genetics (formerly Invitae)

normophosphatemic familial tumoral calcinosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: Genomics England PanelApp

normophosphatemic familial tumoral calcinosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: Orphanet

normophosphatemic familial tumoral calcinosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: ClinGen

SAMD9 was first reported in relation to autosomal recessive normophosphatemic familial tumoral calcinosis in 2006 (Topaz et al., PMID: 16960814). SAMD9 has been associated with MIRAGE syndrome (OMIM 617053), Monosomy 7 myelodysplasia and leukemia syndrome 2 (OMIM 619041), and Tumoral calcinosis, familial, normophosphatemic (OMIM 610455). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, molecular mechanism and phenotypic variability. Therefore, the disease entities have been split into two disease entities by inheritance pattern. The autosomal dominant MIRAGE syndrome and Monosomy 7 myelodysplasia and leukemia syndrome 2 were lumped together while the recessive Tumoral calcinosis, familial, normophosphatemic was split. This curation addresses SAMD9 in relation to normophosphatemic familial tumoral calcinosis. Two unique variants (missense and nonsense) that have been reported in at least 6 probands in 2 publications (PMIDs: 16960814, 18094730) are included in this curation. All probands were of Jewish-Yemenite origin and 5 of the 6 probands were identified to be homozygous for a missense variant. The missense variant has also been reported as a homozygous occurrence in a proband on ClinVar (LabCorp, ClinVar Accession: SCV004294513.1). This gene-disease relationship is also supported by experimental evidence including biochemical function and altered expression in patient cells (PMIDs: 16960814, 18094730). In summary, there is limited evidence supporting the relationship between SAMD9 and autosomal recessive normophosphatemic familial tumoral calcinosis. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date February 11th, 2025 (SOP Version 11).

MIRAGE syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: Orphanet

MIRAGE syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: Labcorp Genetics (formerly Invitae)

monosomy 7 myelodysplasia and leukemia syndrome 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030801

Submitter: Labcorp Genetics (formerly Invitae)

monosomy 7 myelodysplasia and leukemia syndrome 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030801

Submitter: Ambry Genetics

normophosphatemic familial tumoral calcinosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: Ambry Genetics

monosomy 7 myelodysplasia and leukemia syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030801

Submitter: PanelApp Australia

MIRAGE syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: Ambry Genetics

MIRAGE syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: G2P

MIRAGE syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: Genomics England PanelApp

normophosphatemic familial tumoral calcinosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012502

Submitter: PanelApp Australia

MIRAGE syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014888

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mirage syndrome; Monosomy 7 myelodysplasia and leukemia syndrome 2; Tumoral calcinosis, normophosphatemic, familialAD/AR

Manifestation: Allergy/Immunology/Infectious; Dental; Dermatologic; Endocrine; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Endocrine; Hematologic; Musculoskeletal; Oncologic

Rationale: Mirage syndrome can include anemia and thrombocytopenia requiring transfusions; Individuals can have severe and recurrent infections, and awareness may allow preventive measures and early and aggressive treatment of infections; Individuals may have salt-wasting adrenal hypoplasia, and awareness may allow prompt recognition and treatment to manage electrolyte and endocrine sequelae; For individuals with Tumoral calcinosis, surveillance/early treatment of tumoral calcinosis may reduce morbidity; Monosomy 7 myelodysplasia and leukemia syndrome 2 involves germline genetic anomaly as well as associated somatic loss of chromosome 7, and results in increased risk of hematologic malignancy such that awareness may allow early diagnosis and management of disease

Refs: 3366131; 15133511; 16960814; 18094730; 27182967; 28487541; 30046003; 30322869

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SAMD9 variants in ClinVar

16 Conditions Cataloged

Inborn genetic diseasesTotal: 2133

not providedTotal: 1413

not specifiedTotal: 196

SAMD9-related disorderTotal: 161

Normophosphatemic familial tumoral calcinosisTotal: 82

MIRAGE syndromeTotal: 76

Monosomy 7 myelodysplasia and leukemia syndrome 2Total: 61

Hereditary cancer-predisposing syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017654.4. 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			3 clinvar	793 clinvar		796
missense	8 clinvar	29 clinvar	1742 clinvar	102 clinvar	5 clinvar	1886
nonsense		2 clinvar	75 clinvar	1 clinvar		78
start loss			2 clinvar			2
frameshift	1 clinvar	7 clinvar	90 clinvar	2 clinvar		100
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	9	39	1912	898	5	2863

Highest pathogenic variant AF is 0.000037982427

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017654.4	RefSeq	NP_060124.2	1	MANE Select
ENST00000379958.3	Ensembl	ENSP00000369292.2	1	MANE Select
NM_001193307.2	RefSeq	NP_001180236.1	1	Standard
ENST00000446617.1	Ensembl	ENSP00000414529.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

endosomal vesicle fusion

Molecular Function

protein binding

Cellular Component

cytoplasm
cytosol
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379958
Coding exons: 1
Length: 18508
Individuals with no LoFs: 124725
Homozygous LoFs: 6
Heterozygous LoFs: 1008
Defined: 125739
p: 0.00404

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.769	709	769	0.922	0.0000384	10594
Missense (PolyPhen)		173	186.49	0.92767		2651
Synonymous	0.0796	277	279	0.994	0.0000141	2894
Loss of Function	0.104	51	51.8	0.984	0.00000288	751

Population LoF Frequency

Population	CAF	p-value	Status
African	0.033	0.033	notable
Latino/Admixed American	0.0037	0.0036	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0026	0.0026	notable
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.0018	0.0018	notable
South Asian	0.0030	0.0030	notable
Other	0.0028	0.0028	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the inflammatory response to tissue injury and the control of extra-osseous calcification, acting as a downstream target of TNF-alpha signaling. Involved in the regulation of EGR1, in coordination with RGL2. May be involved in endosome fusion. {ECO:0000269|PubMed:16960814, ECO:0000269|PubMed:18094730, ECO:0000269|PubMed:21160498, ECO:0000269|PubMed:24029230}.;
Disease: DISEASE: Tumoral calcinosis, normophosphatemic, familial (NFTC) [MIM:610455]: An uncommon, life-threatening disorder characterized by progressive deposition of calcified masses in cutaneous and subcutaneous tissues. Serum phosphate levels are normal. Clinical features include painful calcified ulcerative lesions and massive calcium deposition in the mid- and lower dermis, severe skin and bone infections, erythematous papular skin eruption in infancy, conjunctivitis, and gingivitis. NFTC shows a striking resemblance to acquired dystrophic calcinosis, in which tissue calcification occurs as a consequence of tissue injury/inflammation. {ECO:0000269|PubMed:16960814, ECO:0000269|PubMed:18094730}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: MIRAGE syndrome (MIRAGE) [MIM:617053]: A form of syndromic adrenal hypoplasia characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. {ECO:0000269|PubMed:27182967}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0928

Intolerance Scores

LoFtool: 0.991
RVIS EVS: 1.12
RVIS percentile EVS: 92.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.258

Gene Damage Prediction

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