SIL1

Chr 5AR

SIL1 nucleotide exchange factor

Also known as: BAP, MSS, ULG5

NCBI Gene: 64374 ENSG00000120725 UniProt: Q9H173 OMIM: 608005

The protein functions as a nucleotide exchange factor for the ER luminal chaperone HSPA5 and is required for protein translocation and folding in the endoplasmic reticulum. Mutations cause Marinesco-Sjögren syndrome, inherited in an autosomal recessive pattern. The pathogenic mechanism appears to be dominant negative.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Marinesco-Sjogren syndromeMIM #248800

UniProtMarinesco-Sjoegren syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Marinesco-Sjogren syndrome · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.64

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — SIL1

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?

0.64LOEUF

pLI 0.012

Z-score 2.79

OE 0.34 (0.19–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.92 (0.82–1.02)

234 obs / 255.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.19–0.64)

0≤0.351.4

Missense OE?0.92 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 7 / 20.7Missense obs/exp: 234 / 255.2Syn Z: -0.64

Background carrier burden — how many people carry a rare variant somewhere in SIL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 84

548 rare PASS variants

Rare truncating (LoF)

1 in 1,100

94 rare PASS variants

Rare synonymous (reference)

1 in 110

281 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIL1. 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 1,900
South Asian	~43k	1 in 79	1 in 240
Remaining (unassigned)	~30k	1 in 68	1 in 720
European (Finnish)	~27k	1 in 560	1 in 520
Admixed American	~22k	1 in 79	1 in 1,900
African / African American	~21k	1 in 82	1 in 890
East Asian	~20k	1 in 76	1 in 480
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 60	≈ 1 in 2,900

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): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓