SYVN1

Chr 11

synoviolin 1

Also known as: DER3, HRD1

NCBI Gene: 84447 ENSG00000162298 UniProt: Q86TM6 OMIM: 608046

The SYVN1 protein is an E3 ubiquitin ligase that degrades misfolded proteins in the endoplasmic reticulum-associated degradation (ERAD) pathway, protecting cells from ER stress-induced apoptosis. Mutations cause autosomal dominant developmental and epileptic encephalopathy with onset in infancy or early childhood. This gene is highly constrained against loss-of-function variants (pLI = 1.00, LOEUF = 0.17), indicating that complete protein loss is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded proteins, accumulated during ER stress, by retrograde transport to the cytosol from the ER. This protein also uses the ubiquitin-proteasome system for additional degradation of unfolded proteins. Sequence analysis identified two transcript variants that encode different isoforms. [provided by RefSeq, May 2011]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 4.70

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.18Z-score

OE missense 0.68 (0.61–0.75)

248 obs / 365.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.68 (0.61–0.75)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 1 / 27.7Missense obs/exp: 248 / 365.4Syn Z: -0.10

Background carrier burden — how many people carry a rare variant somewhere in SYVN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

674 rare PASS variants

Rare truncating (LoF)

1 in 2,300

71 rare PASS variants

Rare synonymous (reference)

1 in 190

335 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SYVN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 5,000
South Asian	~43k	1 in 80	1 in 5,400
Remaining (unassigned)	~30k	1 in 85	≈ 1 in 15,000
European (Finnish)	~27k	1 in 270	1 in 530
Admixed American	~22k	1 in 110	1 in 4,100
African / African American	~21k	1 in 130	1 in 1,300
East Asian	~20k	1 in 110	1 in 2,500
Ashkenazi Jewish	~13k	1 in 200	1 in 2,500
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 15 coding exons well covered in gnomAD exomes; exon 11 marginal. Genomes: 14 of 15 (exon 11 below).? see exons ↓