SMPX

protein-coding

small muscle protein X-linked

Gene summary

This gene encodes a small protein that has no known functional domains. Mutations in this gene are a cause of X-linked deafness-4, and the encoded protein may play a role in the maintenance of inner ear cells subjected to mechanical stress. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:

DFN6

MANE transcript

NM_014332.3

Inheritance

ClinVar variants

P:24U:36B:14

Top phenotype

Deafness, X-linked 4

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:21,705,978-21,758,116

External References & Databases

Ensembl (ENSG00000091482)

Transcript & Mutation Effects

hg38 • Region Span ~52.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, X-linked 4STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010238

Submitter: Labcorp Genetics (formerly Invitae)

myopathy, distal, 7, adult-onset, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024771

Submitter: PanelApp Australia

myopathy, distal, 7, adult-onset, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024771

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, X-linked 4STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010238

Submitter: PanelApp Australia

X-linked nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019586

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between SMPX and X-linked nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 9/8/17. Variants in SMPX were first reported in humans with the disease as early as 2011 (Schraders et al., 21549342). At least six variants, nonsense and frameshift, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported at least 8 probands in 5 publications (21549342, 21549336, 21893181, 22911656, 28542515). Variants in this gene segregated with disease in >100 additional family members. The families studied display an expected-X linked inheritance pattern where the hearing loss is earlier onset and more profound in males and slightly less penetrant in females. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies. Loss of function of SMPX is expected to impact the ability of inner ear hair cells to conduct sound. It is important to note that there were SMPX null mice generated to investigate the effect of the deletion on muscle organization and function, however hearing loss was not studied in these mice (Palmer et al. 2001). In summary, SMPX is definitively associated with X-linked nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 9/12/17.

Clinical Genomic Database (CGD)

Deafness, X-linked 4XL

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment, which may occur in the prelingual stage in some individuals, may improve outcomes, including speech and language development

Comments: Both prelingual and postlingual onset of deafness has been described, with males described as being affected earlier and more severely

Refs: 8872482; 21549336; 21549342; 21893181; 22911656; 33974137

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMPX variants in ClinVar

8 Conditions Cataloged

not providedTotal: 60

Hearing loss, X-linked 4Total: 15

not specifiedTotal: 7

Myopathy, distal, 7, adult-onset, X-linkedTotal: 4

SMPX-related disorderTotal: 4

Inborn genetic diseasesTotal: 3

Hearing impairmentTotal: 2

X-linked deafnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014332.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				13 clinvar		13
missense	3 clinvar	1 clinvar	31 clinvar	1 clinvar		36
nonsense	5 clinvar		2 clinvar			7
start loss						0
frameshift	4 clinvar	7 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	2 clinvar			6
Total	13	11	36	14	0	74

Highest pathogenic variant AF is 0.000013244704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014332.3	RefSeq	NP_055147.1	3	MANE Select
ENST00000379494.4	Ensembl	ENSP00000368808.3	3	MANE Select
ENST00000494525.1	Ensembl	ENSP00000495170.1	3	Standard
ENST00000646008.1	Ensembl	ENSP00000493671.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

striated muscle contraction

Cellular Component

nucleus
muscle tendon junction
M band
costamere

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379494
Coding exons: 3
Length: 52192
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0417	34	33.3	1.02	0.00000240	563
Missense (PolyPhen)		15	13.25	1.132		244
Synonymous	-1.47	20	13.2	1.52	0.00000110	172
Loss of Function	1.63	0	3.11	0.00	1.95e-7	60

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair. {ECO:0000250}.;
Disease: DISEASE: Deafness, X-linked, 4 (DFNX4) [MIM:300066]: A non- syndromic form of sensorineural, progressive hearing loss with postlingual onset. In affected males, the auditory impairment affects initially high-frequency hearing. It later evolves to become severe to profound and affects all frequencies. Carrier females manifest moderate hearing impairment in the high frequencies. {ECO:0000269|PubMed:21549336, ECO:0000269|PubMed:21549342, ECO:0000269|PubMed:22911656}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.421
RVIS EVS: 0.01
RVIS percentile EVS: 54.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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