SAMD9L
protein-codingsterile alpha motif domain containing 9 like, the group of Sterile alpha motif domain containing
Gene summary
This gene encodes a cytoplasmic protein that acts as a tumor suppressor but also plays a key role in cell proliferation and the innate immune response to viral infection. The encoded protein contains an N-terminal sterile alpha motif domain. Naturally occurring mutations in this gene are associated with myeloid disorders such as juvenile myelomonocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. Naturally occurring mutations are also associated with hepatitis-B related hepatocellular carcinoma, normophosphatemic familial tumoral calcinosis, and ataxia-pancytopenia syndrome. [provided by RefSeq, Apr 2017]
- C7orf6
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:1060111
Submitter: ClinGen
SAMD9L was first reported in relation to autosomal dominant SAMD9L-related spectrum and myeloid neoplasm risk in 2016 (Chen et al., PMID: 27259050). SAMD9L-related spectrum and myeloid neoplasm risk was originally reported in 1978 by Li et al., PMID: 283689. Clinical manifestation is characterized by variable presentations of ataxia and cytopenia, myelodysplastic syndrome (MDS), monosomy 7, acute myelogenous leukemia (AML), and bone marrow failure (BMF). The spectrum can include manifestations in multiple organ systems, particularly neurologic, dermatologic and immunologic, with immune deficiency and/or systemic inflammation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: ataxia-pancytopenia syndrome (OMIM:159550), monosomy 7 myelodysplasia and leukemia syndrome 1 (OMIM:252270), and spinocerebellar ataxia 49 (OMIM:619806). Twenty-seven variants (missense and frameshift) that have been reported in twenty-seven probands in seven publications (PMIDs: 27259050, 28202457, 29146900, 30322869, 34621053, 35310830, 37216690) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain of function for onset in childhood, loss of function for onset in adulthood (PMID: 30322869). This gene-disease relationship is also supported by heterozygous and homozygous knockout mice phenocopying human disease as well as expression in child cerebellum as well as embryonic cerebellum and spinal cord tissues (PMIDs: 24029230, 35310830). In summary, there is definitive evidence supporting the relationship between SAMD9L and autosomal dominant SAMD9L-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 January 14, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0008038
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008038
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030805
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008038
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008038
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008038
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: Ataxia-pancytopenia syndrome can include pancytopenia and related infectious risks, and awareness may allow prophylactic measures and early and aggressive treatment of infections and hematologic issues; Individuals have been descriebd with hematologic malignancies, and awareness may allow surveillance and prompt detection and management; Monosomy 7 myelodysplasia and leukemia syndrome 1 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SAMD9L variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152703.5. 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 | 7 | 714 | 721 | |||
| missense | 4 | 18 | 1729 | 143 | 3 | 1897 |
| nonsense | 2 | 57 | 1 | 60 | ||
| start loss | 2 | 2 | ||||
| frameshift | 7 | 64 | 1 | 72 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 4 | 27 | 1860 | 859 | 3 | 2753 |
Highest pathogenic variant AF is 0.0000092984155
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689916.2 | 1 | MANE Select | |
| Ensembl | ENSP00000326247.4 | 1 | MANE Select | |
| RefSeq | NP_001290425.1 | 1 | Standard | |
| RefSeq | NP_001290426.1 | 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
- early endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318238
- Coding exons
- 1
- Length
- 18315
- Individuals with no LoFs
- 124982
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 755
- Defined
- 125738
- p
- 0.00301
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.63 | 661 | 790 | 0.836 | 0.0000385 | 10531 |
| Missense (PolyPhen) | 159 | 196.97 | 0.80725 | 2746 | ||
| Synonymous | -0.511 | 294 | 283 | 1.04 | 0.0000135 | 2889 |
| Loss of Function | 2.86 | 32 | 54.9 | 0.583 | 0.00000297 | 761 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00093 | 0.00092 | rare |
| Latino/Admixed American | 0.0023 | 0.0023 | notable |
| Ashkenazi Jewish | 0.0046 | 0.0046 | notable |
| East Asian | 0.00065 | 0.00065 | rare |
| Finnish | 0.0057 | 0.0056 | notable |
| European (Non-Finnish) | 0.0040 | 0.0039 | notable |
| South Asian | 0.00092 | 0.00092 | rare |
| Other | 0.0025 | 0.0024 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be involved in endosome fusion. Mediates down- regulation of growth factor signaling via internalization of growth factor receptors. {ECO:0000250|UniProtKB:Q69Z37}.;
Recessive Scores
- pRec
- 0.0905
Intolerance Scores
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 50.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.252
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |