SAMHD1

SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1, the group of Sterile alpha motif domain containing

Basic information

Region (hg38): 20:36890228-36951893

Links

ENSG00000101347 ∙ NCBI:25939 ∙ OMIM:606754 ∙ HGNC:15925 ∙ Uniprot:Q9Y3Z3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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

Clinical Genomic Database

Source: CGD

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 ClinVar and linked to the SAMHD1 gene.

• Aicardi-Goutieres syndrome 5 (72 variants)
• not provided (5 variants)
• Cerebral palsy (1 variants)
• Aicardi Goutieres syndrome (1 variants)
• Chilblain lupus 2;Aicardi-Goutieres syndrome 5 (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	224	1	227
missense		8	240	1		249
nonsense	28	5	2			35
start loss			2			2
frameshift	42	3	2			47
inframe indel			5			5
splice donor/acceptor (+/-2bp)	4	19	2		1	26
splice region		1	19	38	1	59
non coding			11	130	26	167
Total	74	35	266	355	28

Highest pathogenic variant AF is 0.0000131

Variants in SAMHD1

This is a list of pathogenic ClinVar variants found in the SAMHD1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-36891924-G-C		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Benign (Jan 12, 2018)
20-36892050-A-G		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 12, 2018)
20-36892061-C-T		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 12, 2018)
20-36892215-C-G		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Uncertain significance (Jan 12, 2018)
20-36892221-T-G		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Uncertain significance (Jan 13, 2018)
20-36892284-G-A		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Uncertain significance (Feb 16, 2018)
20-36892303-G-A		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Benign (Jan 12, 2018)
20-36892396-G-A		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Uncertain significance (Jan 12, 2018)
20-36892427-A-T		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 13, 2018)
20-36892429-T-C		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 13, 2018)
20-36892570-C-T		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 13, 2018)
20-36892644-T-C		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Benign (Jan 12, 2018)
20-36892692-C-T		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Conflicting classifications of pathogenicity (Jan 13, 2018)
20-36892812-G-A		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Benign/Likely benign (Jan 13, 2018)
20-36892828-C-G		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Uncertain significance (Jan 12, 2018)
20-36892837-A-G		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Conflicting classifications of pathogenicity (Jan 12, 2018)
20-36892861-G-T		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5 • not specified	Benign (Mar 19, 2020)
20-36892872-T-C		Aicardi-Goutieres syndrome 5 • Chilblain lupus 2	Benign/Likely benign (Mar 01, 2023)
20-36892887-G-A		Chilblain lupus 2 • Aicardi-Goutieres syndrome 5	Benign (Jan 12, 2018)
20-36892936-A-T		Aicardi-Goutieres syndrome 5	Uncertain significance (Jul 18, 2022)
20-36892937-T-C		Aicardi-Goutieres syndrome 5	Uncertain significance (Sep 13, 2022)
20-36892941-G-A		Aicardi-Goutieres syndrome 5	Likely benign (Jul 14, 2022)
20-36892945-T-C			Uncertain significance (Oct 10, 2018)
20-36892951-A-T		Aicardi-Goutieres syndrome 5	Uncertain significance (Oct 15, 2020)
20-36892953-A-G		Aicardi-Goutieres syndrome 5	Likely benign (Jun 02, 2023)

GnomAD

Source: gnomAD

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: dbNSFP

• 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