SPOCK3

Chr 4

SPARC (osteonectin), cwcv and kazal like domains proteoglycan 3

Also known as: HSAJ1454, TES-3, TICN3

NCBI Gene: 50859 ENSG00000196104 UniProt: Q9BQ16 OMIM: 607989

The protein encoded by this gene is a calcium-binding proteoglycan that inhibits matrix metalloproteinase processing and participates in neurogenesis. Mutations cause autosomal recessive intellectual disability with microcephaly, short stature, and facial dysmorphism. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of a novel family of calcium-binding proteoglycan proteins that contain thyroglobulin type-1 and Kazal-like domains. The encoded protein and may play a role in adult T-cell leukemia by inhibiting the activity of membrane-type matrix metalloproteinases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 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

0.57

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.014

Z-score 3.20

OE 0.32 (0.18–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.39Z-score

OE missense 0.93 (0.83–1.04)

219 obs / 235.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.18–0.57)

0≤0.351.4

Missense OE?0.93 (0.83–1.04)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 8 / 25.4Missense obs/exp: 219 / 235.9Syn Z: -1.65

Background carrier burden — how many people carry a rare variant somewhere in SPOCK3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

600 rare PASS variants

Rare truncating (LoF)

1 in 3,000

69 rare PASS variants

Rare synonymous (reference)

1 in 380

215 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPOCK3. 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 150	1 in 3,000
South Asian	~43k	1 in 120	1 in 2,300
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 29,000
European (Finnish)	~27k	1 in 350	1 in 3,800
Admixed American	~22k	1 in 94	1 in 3,600
African / African American	~21k	1 in 88	1 in 3,900
East Asian	~20k	1 in 140	1 in 3,300
Ashkenazi Jewish	~13k	1 in 700	none seen
Middle Eastern	~2,884	1 in 320	≈ 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): 8 of 10 coding exons well covered in gnomAD exomes; exons 4, 11 marginal. Genomes: all 10.? see exons ↓