NOG

Chr 17AD

noggin

Also known as: SYM1, SYNS1, SYNS1A

The secreted polypeptide, encoded by this gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, this protein may have a principal role in creating morphogenic gradients. The protein appears to have pleiotropic effect, both early in development as well as in later stages. It was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. The results of the mouse knockout of the ortholog suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation. Recently, several dominant human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) were identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region (17q22) as this gene. All of these mutations altered evolutionarily conserved amino acid residues. The amino acid sequence of this human gene is highly homologous to that of Xenopus, rat and mouse. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Brachydactyly, type B2MIM #611377

Multiple synostoses syndrome 1MIM #186500

Stapes ankylosis with broad thumbs and toesMIM #184460

Symphalangism, proximal, 1AMIM #185800

Tarsal-carpal coalition syndromeMIM #186570

UniProtBrachydactyly B2

Active trials

265

ClinVar variants

Pathogenic / LP

1.3

Missense Z

0.42

LOEUF

Pubs (2 yr)

Clinical Summary— NOG

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Gene-Disease Validity (ClinGen)

NOG-related symphalangism spectrum disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

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ClinVar Variants

65 Pathogenic / Likely Pathogenic· 148 VUS of 265 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — NOG

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

ensembl: Error: Ensembl fetch failed: 500 for https://rest.ensembl.org/lookup/symbol/homo_sapiens/NOG?content-type=application/json&expand=1

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.42LOEUF

pLI 0.890

Z-score 2.48

OE 0.00 (0.00–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.32Z-score

OE missense 0.68 (0.58–0.81)

94 obs / 137.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.42)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.58–0.81)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09

0≤1.21.6

LoF obs/exp: 0 / 7.2Missense obs/exp: 94 / 137.5Syn Z: -0.56

ClinVar Variant Classifications

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46

Likely Pathogenic19

VUS148

Likely Benign40

Benign8

Conflicting4

Pathogenic

Likely Pathogenic

148

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	15	22	0	46
Likely Pathogenic	4	10	5	0	19
VUS	0	121	1	26	148
Likely Benign	0	2	0	38	40
Benign	0	3	5	0	8
Conflicting	—				4
Total	13	151	33	64	265

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

View in ClinVar →

Protein Context — Lollipop Plot

NOG · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NOG-related-symphalangism spectrum disorder

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersSkeletal

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

NOGGIN; NOG

MIM #602991 · *

Brachydactyly, type B2

MIM #611377