SYNE4

protein-coding

spectrin repeat containing nuclear envelope family member 4, the group of Spectrin repeat containing nuclear envelope family|KASH domain containing

Gene summary

This gene is a member of the nesprin family of genes, that encode KASH (Klarsicht, Anc-1, Syne Homology) domain-containing proteins. In addition to the KASH domain, this protein also contains a coiled-coil and leucine zipper region, a spectrin repeat, and a kinesin-1 binding region. This protein localizes to the outer nuclear membrane, and is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. LINC complexes are formed by SUN (Sad1, UNC-84)-KASH pairs, and are thought to mechanically couple nuclear components to the cytoskeleton. Mutations in this gene have been associated with progressive high-frequency hearing loss. The absence of this protein in mice also caused hearing loss, and changes in hair cell morphology in the ears. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Previous symbols:

C19orf46
DFNB76

MANE transcript

NM_001039876.3

Inheritance

ClinVar variants

P:45U:111B:133

Top phenotype

Deafness, autosomal recessive, 76

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr19:36,003,307-36,008,813

External References & Databases

Ensembl (ENSG00000181392)

Transcript & Mutation Effects

hg38 • Region Span ~5.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014237

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014237

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

SYNE4 was reported in relation to autosomal recessive nonsyndromic hearing loss in 2013 (Horn et al., PMID: 23348741). At least 2 unique variants (frameshift and splice) have been reported in humans. Variants in this gene have been reported in at least 3 probands in 2 publications (PMID: 23348741, 28958982). Variants in this gene segregated with disease in 4 additional family members. The mechanism for disease is homozygous loss of function. This gene-disease association is supported by mouse models and expression studies (PMID: 23348741). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 2/6/2020.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive, 76AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 23348741

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYNE4 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 280

not specifiedTotal: 114

SYNE4-related disorderTotal: 36

Autosomal recessive nonsyndromic hearing loss 76Total: 22

Nonsyndromic genetic hearing lossTotal: 7

Rare genetic deafnessTotal: 1

SYNE4-related hearing lossTotal: 1

Monogenic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039876.3. 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			4 clinvar	110 clinvar	2 clinvar	116
missense			102 clinvar	20 clinvar	1 clinvar	123
nonsense	10 clinvar	6 clinvar	2 clinvar			18
start loss						0
frameshift	10 clinvar	9 clinvar	1 clinvar			20
splice donor/acceptor (+/-2bp)	1 clinvar	9 clinvar	2 clinvar			12
Total	21	24	111	130	3	289

Highest pathogenic variant AF is 0.0007875397

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039876.3	RefSeq	NP_001034965.1	8	MANE Select
ENST00000324444.9	Ensembl	ENSP00000316130.3	8	MANE Select
NM_001297735.3	RefSeq	NP_001284664.1	6	Standard
ENST00000340477.10	Ensembl	ENSP00000343152.5	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

establishment of epithelial cell apical/basal polarity

Molecular Function

protein binding

Cellular Component

integral component of nuclear outer membrane
meiotic nuclear membrane microtubule tethering complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324444
Coding exons: 8
Length: 5487
Individuals with no LoFs: 124663
Homozygous LoFs: 0
Heterozygous LoFs: 127
Defined: 124790
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.492	208	229	0.908	0.0000134	2509
Missense (PolyPhen)		66	75.38	0.87556		829
Synonymous	-0.972	109	96.8	1.13	0.00000557	873
Loss of Function	0.507	19	21.5	0.882	0.00000126	200

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00066	0.00058	rare
Latino/Admixed American	0.00016	0.00014	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00029	0.00028	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00090	0.00082	rare
South Asian	0.00020	0.00020	rare
Other	0.00088	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning (By similarity). Behaves as a kinesin cargo, providing a functional binding site for kinesin-1 at the nuclear envelope. Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity). {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 76 (DFNB76) [MIM:615540]: A form of non-syndromic sensorineural deafness, a disorder resulting from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB76 affected individuals have onset of progressive high frequency hearing impairment between birth and 6 years of age. The hearing loss is severe at high frequencies by adulthood. {ECO:0000269|PubMed:23348741}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.35
RVIS percentile EVS: 74.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

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