SMCHD1

structural maintenance of chromosomes flexible hinge domain containing 1

Basic information

Region (hg38): 18:2655726-2805017

Links

ENSG00000101596 ∙ NCBI:23347 ∙ OMIM:614982 ∙ HGNC:29090 ∙ Uniprot:A6NHR9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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
• arhinia, choanal atresia, and microphthalmia (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

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 ClinVar and linked to the SMCHD1 gene.

• Facioscapulohumeral_muscular_dystrophy_2 (1143 variants)
• not_provided (459 variants)
• Inborn_genetic_diseases (155 variants)
• not_specified (44 variants)
• Arrhinia_with_choanal_atresia_and_microphthalmia_syndrome (35 variants)
• SMCHD1-related_disorder (31 variants)
• Scapulohumeral_muscular_dystrophy (12 variants)
• Abnormality_of_the_musculature (2 variants)
• Scapular_winging (2 variants)
• Anosmia (2 variants)
• Short_nose (2 variants)
• Ch�diak-Higashi_syndrome (2 variants)
• Muscle_weakness (2 variants)
• Male_infertility_with_azoospermia_or_oligozoospermia_due_to_single_gene_mutation (1 variants)
• Proximal_muscle_weakness_in_upper_limbs (1 variants)
• Cryptorchidism (1 variants)
• See_cases (1 variants)
• Muscular_atrophy (1 variants)
• Weakness_of_facial_musculature (1 variants)
• Microphallus (1 variants)
• Muscular_dystrophy (1 variants)
• Shoulder_girdle_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. These statistics are base on transcript: NM_000015295.3. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1		22	245	8	276
missense	18	8	666	22	1	715
nonsense	20	5	1			26
start loss			1			1
frameshift	38	10	2			50
splice donor/acceptor (+/-2bp)	10	15	4		1	30
Total	87	38	696	267	10

Highest pathogenic variant AF is 0.0000065810254

GnomAD

Source: gnomAD

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: dbNSFP

• 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