SHMT2

serine hydroxymethyltransferase 2, the group of Serine hydroxymethyltransferase family

Basic information

Region (hg38): 12:57229573-57234935

Previous symbols: [ "SHMT" ]

Links

ENSG00000182199 ∙ NCBI:6472 ∙ OMIM:138450 ∙ HGNC:10852 ∙ Uniprot:P34897 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Moderate), mode of inheritance: AR
• neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (Strong), mode of inheritance: AR
• neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities	AR	Cardiovascular	Among other findings, the condition can include progressive cardiomyopathy, and awareness may allow early diagnosis and management; Cardiac transplant has been described	Cardiovascular; Musculoskeletal; Neurologic	33015733

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SHMT2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SHMT2 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	2
missense		3	29	3	1	36
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	1	1	3
non coding					4	4
Total	0	3	31	3	7

Variants in SHMT2

This is a list of pathogenic ClinVar variants found in the SHMT2 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-57229580-A-G			Benign (May 16, 2021)
12-57229736-G-A			Benign (May 16, 2021)
12-57230839-A-G		Inborn genetic diseases	Uncertain significance (Jan 27, 2022)
12-57230842-C-T		Inborn genetic diseases	Uncertain significance (Apr 10, 2023)
12-57230845-G-T		Inborn genetic diseases	Uncertain significance (Dec 21, 2023)
12-57230859-C-A		Inborn genetic diseases	Likely benign (Oct 03, 2022)
12-57230889-CAG-C		not specified	Uncertain significance (Jan 12, 2024)
12-57230918-C-T			Benign (May 04, 2021)
12-57230920-G-C		Inborn genetic diseases	Uncertain significance (Aug 20, 2023)
12-57231494-G-T		Inborn genetic diseases	Uncertain significance (Dec 11, 2023)
12-57231530-A-G		Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities	Uncertain significance (Jan 11, 2024)
12-57231545-G-T		Inborn genetic diseases	Uncertain significance (Oct 09, 2024)
12-57231707-C-T			Benign (Mar 30, 2018)
12-57231720-G-A		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
12-57231749-G-A			Likely benign (Sep 01, 2024)
12-57231762-C-T		SHMT2-related disorder	Likely benign (Jan 03, 2023)
12-57231787-T-G			Uncertain significance (Jun 03, 2022)
12-57231793-C-T		Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
12-57231828-G-A			Uncertain significance (Jun 03, 2022)
12-57231843-C-G		Inborn genetic diseases	Uncertain significance (Mar 01, 2024)
12-57231849-G-A		Inborn genetic diseases	Uncertain significance (Jun 06, 2023)
12-57231853-A-G		Inborn genetic diseases	Uncertain significance (Aug 20, 2024)
12-57231870-C-T		Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities	Pathogenic (Dec 11, 2020)
12-57232167-G-A			Benign (May 16, 2021)
12-57232235-C-T			Benign (May 05, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SHMT2	protein_coding	protein_coding	ENST00000328923	12	5609

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.82e-8	0.977	125711	0	37	125748	0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.52	234	309	0.756	0.0000194	3234
Missense in Polyphen		88	137.89	0.63817		1442
Synonymous	-0.677	131	122	1.08	0.00000704	1063
Loss of Function	2.16	16	28.4	0.563	0.00000186	276

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000359	0.000359
Ashkenazi Jewish	0.0000996	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000159	0.000158
Middle Eastern	0.0000544	0.0000544
South Asian	0.000196	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:29364879, PubMed:25619277). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism: thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Also required for mitochondrial translation by producing 5,10- methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29452640, PubMed:29364879). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondria, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985). {ECO:0000269|PubMed:18063578, ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:25619277, ECO:0000269|PubMed:29364879, ECO:0000269|PubMed:29452640}.
• Pathway: One carbon pool by folate - Homo sapiens (human);Glycine, serine and threonine metabolism - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);3-Phosphoglycerate dehydrogenase deficiency;Non Ketotic Hyperglycinemia;Glycine and Serine Metabolism;sarcosine oncometabolite pathway ;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Dihydropyrimidine Dehydrogenase Deficiency (DHPD);Glycine Metabolism;Vitamin B12 Metabolism;Folate Metabolism;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;One carbon metabolism and related pathways;Pathways in clear cell renal cell carcinoma;folate polyglutamylation;Folate metabolism;glycine/serine biosynthesis;Glycine Serine metabolism;Metabolism;Lysine degradation;folate transformations I;glycine betaine degradation;Metabolism of folate and pterines;dTMP <i>de novo</i> biosynthesis (mitochondrial);Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;superpathway of choline degradation to L-serine;Lysine metabolism;Vitamin B9 (folate) metabolism;serine and glycine biosynthesis (Consensus)

Recessive Scores

• pRec: 0.395

Intolerance Scores

• loftool: 0.822
• rvis_EVS: -0.11
• rvis_percentile_EVS: 45.26

Haploinsufficiency Scores

• pHI: 0.179
• hipred: Y
• hipred_score: 0.765
• ghis: 0.600

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.923

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Shmt2
• Phenotype: embryo phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: regulation of oxidative phosphorylation;glycine metabolic process;L-serine metabolic process;L-serine biosynthetic process;L-serine catabolic process;one-carbon metabolic process;positive regulation of cell population proliferation;glycine biosynthetic process from serine;response to type I interferon;tetrahydrofolate interconversion;tetrahydrofolate metabolic process;folic acid metabolic process;protein tetramerization;protein homotetramerization;regulation of mitochondrial translation;protein K63-linked deubiquitination;regulation of aerobic respiration;cellular response to tetrahydrofolate
• Cellular component: nucleus;cytoplasm;mitochondrion;mitochondrial inner membrane;mitochondrial intermembrane space;mitochondrial matrix;microtubule cytoskeleton;mitochondrial nucleoid;extracellular exosome;BRISC complex
• Molecular function: chromatin binding;glycine hydroxymethyltransferase activity;protein binding;zinc ion binding;L-allo-threonine aldolase activity;amino acid binding;pyridoxal phosphate binding;identical protein binding;cobalt ion binding;serine binding