SMCHD1
structural maintenance of chromosomes flexible hinge domain containing 1
Basic information
Region (hg38): 18:2655725-2805017
Links
Phenotypes
GenCC
Source:
- arhinia, choanal atresia, and microphthalmia (Strong), mode of inheritance: AD
- arhinia, choanal atresia, and microphthalmia (Strong), mode of inheritance: AD
- facioscapulohumeral muscular dystrophy (Supportive), mode of inheritance: AD
- hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome (Supportive), mode of inheritance: AD
- arhinia, choanal atresia, and microphthalmia (Strong), mode of inheritance: AD
- arhinia, choanal atresia, and microphthalmia (Strong), mode of inheritance: AD
- arhinia, choanal atresia, and microphthalmia (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Bosma arhinia microphthalmia syndrome | AD | Endocrine | The condition involves hypogonadotropic hypogonadism, and in order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required | Craniofacial; Endocrine; Musculoskeletal; Ophthalmologic | 23143600; 28067909; 28067911 |
ClinVar
This is a list of variants' phenotypes submitted to
- Facioscapulohumeral muscular dystrophy 2 (846 variants)
- not provided (520 variants)
- not specified (51 variants)
- Inborn genetic diseases (48 variants)
- Arrhinia with choanal atresia and microphthalmia syndrome (23 variants)
- SMCHD1-related condition (8 variants)
- Facioscapulohumeral muscular dystrophy 2;Arrhinia with choanal atresia and microphthalmia syndrome (3 variants)
- Scapulohumeral muscular dystrophy (3 variants)
- Abnormality of the musculature (2 variants)
- Anosmia (1 variants)
- Cryptorchidism;Short nose;Microphallus (1 variants)
- Arrhinia with choanal atresia and microphthalmia syndrome;Facioscapulohumeral muscular dystrophy 2 (1 variants)
- Shoulder girdle muscle weakness (1 variants)
- See cases (1 variants)
- Scapular winging (1 variants)
- Muscle weakness (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMCHD1 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 | 20 | 138 | 12 | 170 | ||
| missense | 478 | 492 | ||||
| nonsense | 16 | 20 | ||||
| start loss | 1 | |||||
| frameshift | 25 | 34 | ||||
| inframe indel | 9 | |||||
| splice donor/acceptor (+/-2bp) | 10 | 20 | ||||
| splice region ? | 2 | 35 | 37 | 4 | 78 | |
| non coding ? | 191 | 123 | 319 | |||
| Total | 53 | 19 | 517 | 337 | 139 |
Highest pathogenic variant AF is 0.00000659
Variants in SMCHD1
This is a list of pathogenic ClinVar variants found in the SMCHD1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 18-2656077-T-G | Uncertain significance (Jan 11, 2017) | |||
| 18-2656086-C-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Aug 09, 2023) | ||
| 18-2656090-C-A | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Oct 17, 2022) | ||
| 18-2656090-C-T | Facioscapulohumeral muscular dystrophy 2 | Likely benign (Jun 22, 2023) | ||
| 18-2656092-G-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Oct 03, 2023) | ||
| 18-2656094-G-A | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Nov 08, 2022) | ||
| 18-2656099-G-T | Facioscapulohumeral muscular dystrophy 2 | Likely benign (Dec 15, 2023) | ||
| 18-2656102-T-C | Facioscapulohumeral muscular dystrophy 2 | Likely benign (Dec 30, 2022) | ||
| 18-2656104-G-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Jul 05, 2022) | ||
| 18-2656103-G-GGTGGGGCCTCT | Likely pathogenic (Dec 16, 2021) | |||
| 18-2656109-G-A | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Aug 29, 2022) | ||
| 18-2656110-C-A | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Jun 13, 2022) | ||
| 18-2656112-T-G | Facioscapulohumeral muscular dystrophy 2 • SMCHD1-related disorder • Inborn genetic diseases | Uncertain significance (Mar 07, 2024) | ||
| 18-2656113-C-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Apr 06, 2022) | ||
| 18-2656115-G-A | Facioscapulohumeral muscular dystrophy 2 • Inborn genetic diseases | Uncertain significance (Oct 07, 2023) | ||
| 18-2656118-G-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Oct 17, 2022) | ||
| 18-2656120-G-A | Facioscapulohumeral muscular dystrophy 2 | Likely benign (Nov 03, 2022) | ||
| 18-2656122-C-G | Inborn genetic diseases | Uncertain significance (Feb 07, 2023) | ||
| 18-2656122-C-T | Uncertain significance (Mar 03, 2020) | |||
| 18-2656123-TGAG-T | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Aug 17, 2023) | ||
| 18-2656129-G-C | not specified • Facioscapulohumeral muscular dystrophy 2 | Likely benign (Dec 01, 2023) | ||
| 18-2656130-G-C | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Jul 08, 2023) | ||
| 18-2656138-A-G | Facioscapulohumeral muscular dystrophy 2 | Conflicting classifications of pathogenicity (Feb 14, 2023) | ||
| 18-2656146-G-A | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Apr 17, 2023) | ||
| 18-2656149-A-G | Facioscapulohumeral muscular dystrophy 2 | Uncertain significance (Feb 01, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SMCHD1 | protein_coding | protein_coding | ENST00000320876 | 48 | 149279 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 1.14e-10 | 124617 | 0 | 19 | 124636 | 0.0000762 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.63 | 634 | 949 | 0.668 | 0.0000477 | 13124 |
| Missense in Polyphen | 116 | 344.4 | 0.33682 | 4768 | ||
| Synonymous | 0.800 | 302 | 320 | 0.943 | 0.0000162 | 3681 |
| Loss of Function | 8.56 | 9 | 102 | 0.0878 | 0.00000557 | 1395 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000192 | 0.000187 |
| Ashkenazi Jewish | 0.000310 | 0.000298 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.000186 | 0.000186 |
| European (Non-Finnish) | 0.0000672 | 0.0000619 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.0000334 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture (By similarity). Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments (By similarity). Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin (PubMed:23542155). Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X (By similarity). Required to facilitate Xist RNA spreading (By similarity). Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus (PubMed:23143600). Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation (PubMed:29748383). Also plays a role in DNA repair: localizes to sites of DNA double- strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks (PubMed:25294876, PubMed:24790221). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (PubMed:25294876). {ECO:0000250|UniProtKB:Q6P5D8, ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:23542155, ECO:0000269|PubMed:24790221, ECO:0000269|PubMed:25294876, ECO:0000269|PubMed:29748383}.;
- Disease
- DISEASE: Facioscapulohumeral muscular dystrophy 2 (FSHD2) [MIM:158901]: A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:24128691, ECO:0000269|PubMed:25256356, ECO:0000269|PubMed:25370034, ECO:0000269|PubMed:27059856, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMCHD1 mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression (PubMed:23143600). Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death (PubMed:23143600). FSHD2 and FSHD1 share a common pathophysiological pathway in which the FSHD2 gene SMCHD1 can act as a modifier for disease severity in families affected by FSHD1 (PubMed:24075187, PubMed:25370034). {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:25370034}.; DISEASE: Bosma arhinia microphthalmia syndrome (BAMS) [MIM:603457]: An autosomal dominant syndrome characterized by severe hypoplasia of the nose, palatal abnormalities, hypoplasia of the eyes, sensory abnormalities of taste and smell, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. {ECO:0000269|PubMed:28067909, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.114
Intolerance Scores
- loftool
- 0.236
- rvis_EVS
- -1.7
- rvis_percentile_EVS
- 2.57
Haploinsufficiency Scores
- pHI
- 0.946
- hipred
- Y
- hipred_score
- 0.662
- ghis
- 0.649
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Smchd1
- Phenotype
- embryo phenotype; pigmentation phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); 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); reproductive system phenotype; cellular phenotype;
Zebrafish Information Network
- Gene name
- smchd1
- Affected structure
- ethmoid cartilage
- Phenotype tag
- abnormal
- Phenotype quality
- decreased width
Gene ontology
- Biological process
- double-strand break repair;dosage compensation by inactivation of X chromosome;nose development;positive regulation of DNA repair;inactivation of X chromosome by heterochromatin assembly;inactivation of X chromosome by DNA methylation;heterochromatin organization involved in chromatin silencing;negative regulation of double-strand break repair via homologous recombination;positive regulation of double-strand break repair via nonhomologous end joining
- Cellular component
- nuclear chromosome, telomeric region;Barr body;site of double-strand break
- Molecular function
- DNA binding;protein binding;ATP binding;ATPase activity;protein homodimerization activity