SAMHD1
SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1, the group of Sterile alpha motif domain containing
Basic information
Region (hg38): 20:36890229-36951893
Links
Phenotypes
GenCC
Source:
- chilblain lupus (Disputed Evidence), mode of inheritance: AD
- Aicardi-Goutieres syndrome 5 (Strong), mode of inheritance: AR
- Moyamoya disease (Strong), mode of inheritance: AR
- Aicardi-Goutieres syndrome 5 (Strong), mode of inheritance: AR
- Aicardi-Goutieres syndrome (Supportive), mode of inheritance: AD
- familial chilblain lupus (Supportive), mode of inheritance: AD
- Aicardi-Goutieres syndrome 5 (Definitive), mode of inheritance: AR
- chilblain lupus 2 (Limited), mode of inheritance: AD
- Aicardi-Goutieres syndrome 5 (Strong), mode of inheritance: AR
- Aicardi-Goutieres syndrome 5 (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Aicardi-Goutieres syndrome 5 | AR | Cardiovascular | For Aicardi-Goutieres syndrome related to mutations in SAMHD1, it has been suggested that individuals should be actively screened for intracranial arteriopathy in order to allow prompt intervention, which may reduce morbidity and mortality | Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Neurologic | 19525956; 20301648; 20358604; 20653736; 20842748; 21102625; 21402907; 21204240; 21633013; 22149989 |
ClinVar
This is a list of variants' phenotypes submitted to
- Aicardi-Goutieres_syndrome_5 (814 variants)
- Aicardi_Goutieres_syndrome (116 variants)
- not_provided (61 variants)
- Chilblain_lupus_2 (49 variants)
- Inborn_genetic_diseases (45 variants)
- not_specified (22 variants)
- SAMHD1-related_disorder (18 variants)
- Multiple_myeloma (1 variants)
- Cerebral_palsy (1 variants)
- See_cases (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SAMHD1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000015474.4. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 18 | 247 | 269 | |||
| missense | 12 | 284 | 12 | 309 | ||
| nonsense | 28 | 38 | ||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 45 | 55 | ||||
| splice donor/acceptor (+/-2bp) | 19 | 29 | ||||
| Total | 80 | 48 | 312 | 259 | 3 |
Highest pathogenic variant AF is 0.00013202163
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SAMHD1 | protein_coding | protein_coding | ENST00000262878 | 16 | 61615 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 6.45e-13 | 0.828 | 125694 | 0 | 54 | 125748 | 0.000215 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.55 | 267 | 348 | 0.767 | 0.0000195 | 4143 |
| Missense in Polyphen | 47 | 75.902 | 0.61922 | 897 | ||
| Synonymous | 0.892 | 107 | 119 | 0.896 | 0.00000656 | 1151 |
| Loss of Function | 1.86 | 25 | 37.2 | 0.671 | 0.00000230 | 412 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000391 | 0.000391 |
| Ashkenazi Jewish | 0.000198 | 0.000198 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.0000925 | 0.0000924 |
| European (Non-Finnish) | 0.000334 | 0.000334 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.0000653 | 0.0000653 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:22056990, PubMed:24336198, PubMed:26294762, PubMed:26431200, PubMed:28229507, PubMed:28834754, PubMed:29670289). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses, such as HIV-1: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:23364794, PubMed:25038827, PubMed:26101257, PubMed:22056990, PubMed:24336198, PubMed:28229507, PubMed:26294762, PubMed:26431200). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:24035396, PubMed:29610582, PubMed:24217394). Not able to restrict infection by HIV-2 virus; because restriction activity is counteracted by HIV-2 viral protein Vpx (PubMed:21613998, PubMed:21720370). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (PubMed:23858451). Phosphorylation at Thr-592 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks (PubMed:23602554, PubMed:23601106, PubMed:29610582, PubMed:29670289). Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication (PubMed:29670289). Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation (PubMed:27477283, PubMed:29670289). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (PubMed:29670289). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (By similarity). {ECO:0000250|UniProtKB:Q60710, ECO:0000269|PubMed:19525956, ECO:0000269|PubMed:21613998, ECO:0000269|PubMed:21720370, ECO:0000269|PubMed:22056990, ECO:0000269|PubMed:23364794, ECO:0000269|PubMed:23601106, ECO:0000269|PubMed:23602554, ECO:0000269|PubMed:23858451, ECO:0000269|PubMed:24035396, ECO:0000269|PubMed:24217394, ECO:0000269|PubMed:24336198, ECO:0000269|PubMed:25038827, ECO:0000269|PubMed:26101257, ECO:0000269|PubMed:26294762, ECO:0000269|PubMed:26431200, ECO:0000269|PubMed:27477283, ECO:0000269|PubMed:28229507, ECO:0000269|PubMed:28834754, ECO:0000269|PubMed:29610582, ECO:0000269|PubMed:29670289}.;
- Disease
- DISEASE: Aicardi-Goutieres syndrome 5 (AGS5) [MIM:612952]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269|PubMed:19525956, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:20842748, ECO:0000269|PubMed:24035396, ECO:0000269|PubMed:24183309, ECO:0000269|PubMed:28229507, ECO:0000269|PubMed:29670289}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Chilblain lupus 2 (CHBL2) [MIM:614415]: A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. {ECO:0000269|PubMed:21204240}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Cytokine Signaling in Immune system;Nucleobase catabolism;Metabolism of nucleotides;Immune System;Metabolism;Interferon alpha/beta signaling;Interferon Signaling
(Consensus)
Recessive Scores
- pRec
- 0.136
Intolerance Scores
- loftool
- 0.247
- rvis_EVS
- -0.73
- rvis_percentile_EVS
- 14.02
Haploinsufficiency Scores
- pHI
- 0.0444
- hipred
- N
- hipred_score
- 0.398
- ghis
- 0.559
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.855
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Samhd1
- Phenotype
- cellular phenotype; normal phenotype; immune system phenotype;
Zebrafish Information Network
- Gene name
- samhd1
- Affected structure
- fourth ventricle
- Phenotype tag
- abnormal
- Phenotype quality
- swollen
Gene ontology
- Biological process
- double-strand break repair via homologous recombination;dGTP catabolic process;immune response;cellular response to DNA damage stimulus;deoxyribonucleotide catabolic process;somatic hypermutation of immunoglobulin genes;regulation of innate immune response;dATP catabolic process;protein homotetramerization;defense response to virus;type I interferon signaling pathway;negative regulation of type I interferon-mediated signaling pathway;RNA phosphodiester bond hydrolysis;DNA strand resection involved in replication fork processing
- Cellular component
- nucleus;nucleoplasm;plasma membrane;site of double-strand break
- Molecular function
- nucleic acid binding;single-stranded DNA binding;RNA binding;ribonuclease activity;protein binding;GTP binding;zinc ion binding;dGTPase activity;triphosphoric monoester hydrolase activity;dGTP binding;identical protein binding