SYNE4

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

Basic information

Region (hg38): 19:36003307-36008813

Previous symbols: [ "C19orf46", "DFNB76" ]

Links

ENSG00000181392 ∙ NCBI:163183 ∙ OMIM:615535 ∙ HGNC:26703 ∙ Uniprot:Q8N205 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive nonsyndromic hearing loss 76 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 76 (Strong), mode of inheritance: AR
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive, 76	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic	23348741

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SYNE4 gene.

• not provided (24 variants)
• Autosomal recessive nonsyndromic hearing loss 76 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SYNE4 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			1	90	5	96
missense			49	9	2	60
nonsense	10	2				12
start loss						0
frameshift	13	2	1			16
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	5	1			7
splice region			1	9		10
non coding				45	8	53
Total	24	9	53	144	15

Highest pathogenic variant AF is 0.0000328

Variants in SYNE4

This is a list of pathogenic ClinVar variants found in the SYNE4 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-36003332-A-G		not specified • SYNE4-related disorder	Benign (Feb 04, 2020)
19-36003343-T-G			Likely benign (Oct 04, 2023)
19-36003356-T-C			Uncertain significance (Jul 08, 2022)
19-36003365-C-T			Uncertain significance (Dec 06, 2022)
19-36003378-AG-A		not specified	Uncertain significance (Feb 20, 2023)
19-36003395-C-G			Uncertain significance (May 28, 2024)
19-36003395-C-T		not specified	Likely benign (Jul 15, 2020)
19-36003406-G-A			Likely benign (Apr 18, 2023)
19-36003418-T-A			Likely benign (Mar 03, 2023)
19-36003420-C-T			Uncertain significance (Sep 07, 2022)
19-36003424-C-T			Likely benign (Jan 31, 2024)
19-36003425-G-A		not specified	Conflicting classifications of pathogenicity (May 18, 2023)
19-36003427-G-A			Benign (Dec 14, 2023)
19-36003450-C-T		not specified • SYNE4-related disorder	Conflicting classifications of pathogenicity (Jan 30, 2024)
19-36003451-C-A			Likely benign (Oct 07, 2023)
19-36003453-G-A			Likely benign (Jun 16, 2023)
19-36003453-GGAGGAGGAA-G			Uncertain significance (Jan 25, 2022)
19-36003463-G-T			Likely benign (Jan 15, 2024)
19-36003472-G-C			Likely benign (Jan 29, 2024)
19-36003474-G-T			Likely benign (Jan 25, 2024)
19-36003490-C-T			Likely benign (Sep 29, 2023)
19-36003492-G-A			Likely benign (Jul 30, 2023)
19-36003502-G-A			Likely benign (Jul 15, 2023)
19-36003504-A-G		not specified	Uncertain significance (Jan 03, 2024)
19-36003513-C-T			Uncertain significance (Dec 08, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SYNE4	protein_coding	protein_coding	ENST00000324444	8	5487

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.19e-12	0.0962	124663	0	127	124790	0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.492	208	229	0.908	0.0000134	2509
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000819	0.000744
Ashkenazi Jewish	0.000108	0.0000993
East Asian	0.000292	0.000278
Finnish	0.000143	0.000139
European (Non-Finnish)	0.000900	0.000821
Middle Eastern	0.000292	0.000278
South Asian	0.000201	0.000196
Other	0.000877	0.000825

dbNSFP

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

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.123
• ghis: 0.449

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Syne4
• Phenotype: hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: establishment of epithelial cell apical/basal polarity
• Cellular component: integral component of nuclear outer membrane;meiotic nuclear membrane microtubule tethering complex
• Molecular function: protein binding