SYNE4

Chr 19AR

spectrin repeat containing nuclear envelope family member 4

Also known as: C19orf46, DFNB76, KASH4, Nesp4

NCBI Gene: 163183 ENSG00000181392 UniProt: Q8N205 OMIM: 615535

The protein functions as a component of the LINC complex that connects the nuclear lamina to the cytoskeleton, transmits mechanical forces across the nuclear envelope, and serves as a kinesin cargo to promote proper cellular organization in secretory epithelial cells. Mutations cause autosomal recessive deafness (DFNB76), indicating a critical role in inner ear function. The gene shows low constraint to loss-of-function variation, consistent with the recessive inheritance pattern observed clinically.

GeneReviews OMIM ResearchSummary from OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.291 OMIM phenotype

Clinical Summary— SYNE4

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 103 VUS of 365 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SYNE4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.29LOEUF

pLI 0.000

Z-score 0.51

OE 0.88 (0.61–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.49Z-score

OE missense 0.91 (0.81–1.02)

208 obs / 229.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.61–1.29)

0≤0.351.4

Missense OE?0.91 (0.81–1.02)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 19 / 21.5Missense obs/exp: 208 / 229.0Syn Z: -0.97

This gene — mechanism propensity

0.6356th %ile

GOF

0.76top 25%

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

365 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic23

VUS103

Likely Benign174

Benign16

Conflicting19

Pathogenic

Likely Pathogenic

103

VUS

174

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	0	1	0	20
Likely Pathogenic	22	0	1	0	23
VUS	1	96	5	1	103
Likely Benign	0	10	60	104	174
Benign	0	2	9	5	16
Conflicting	—				19
Total	42	108	76	110	355

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

13 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SYNE4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →